Dépouillements

Sex differences in brain structure: a twin study on restricted and repetitive behaviors in twin pairs with and without autism / A. VAN'T WESTEINDE in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 1 p. Titre : Sex differences in brain structure: a twin study on restricted and repetitive behaviors in twin pairs with and without autism Type de document : Texte imprimé et/ou numérique Auteurs : A. VAN'T WESTEINDE, Auteur ; Elodie CAUVET, Auteur ; R. TORO, Auteur ; R. KUJA-HALKOLA, Auteur ; J. NEUFELD, Auteur ; K. MEVEL, Auteur ; Sven BÖLTE, Auteur Article en page(s) : 1 p. Langues : Anglais (eng) Mots-clés : Autism  Neuroanatomy  Repetitive behaviors  Sex differences  Twins Index. décimale : PER Périodiques Résumé : Background: Females with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex-specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors. Methods: In 75 twin pairs (n = 150, 62 females, 88 males) enriched for autism spectrum disorder (n = 32), and other neurodevelopmental disorders (n = 32), we explored the association of restricted and repetitive behaviors and interests-operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale)-with cortical volume, surface area and thickness of neocortical, sub-cortical, and cerebellar networks. Results: Co-twin control analyses revealed within-pair associations between RRBI symptoms and increased thickness of the right intraparietal sulcus and reduced volume of the right orbital gyrus in females only, even though the mean number of RRBIs did not differ between the sexes. In a sub-sample of ASD-discordant pairs, increased thickness in association with RRBIs was found exclusively in females in the orbitofrontal regions, superior frontal gyrus, and intraparietal sulcus, while in males RRBIs tended to be associated with increased volume of the bilateral pallidum. Limitations: However, due to a small sample size and the small difference in RRBI symptoms within pairs, the results of this exploratory study need to be interpreted with caution. Conclusions: Our findings suggest that structural alterations of fronto-parietal networks in association with RRBIs are found mostly in females, while striatal networks are more affected in males. These results endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males. En ligne : http://dx.doi.org/10.1186/s13229-019-0309-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 [article] Sex differences in brain structure: a twin study on restricted and repetitive behaviors in twin pairs with and without autism [Texte imprimé et/ou numérique] / A. VAN'T WESTEINDE, Auteur ; Elodie CAUVET, Auteur ; R. TORO, Auteur ; R. KUJA-HALKOLA, Auteur ; J. NEUFELD, Auteur ; K. MEVEL, Auteur ; Sven BÖLTE, Auteur . - 1 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 1 p. Mots-clés : Autism  Neuroanatomy  Repetitive behaviors  Sex differences  Twins Index. décimale : PER Périodiques Résumé : Background: Females with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex-specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors. Methods: In 75 twin pairs (n = 150, 62 females, 88 males) enriched for autism spectrum disorder (n = 32), and other neurodevelopmental disorders (n = 32), we explored the association of restricted and repetitive behaviors and interests-operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale)-with cortical volume, surface area and thickness of neocortical, sub-cortical, and cerebellar networks. Results: Co-twin control analyses revealed within-pair associations between RRBI symptoms and increased thickness of the right intraparietal sulcus and reduced volume of the right orbital gyrus in females only, even though the mean number of RRBIs did not differ between the sexes. In a sub-sample of ASD-discordant pairs, increased thickness in association with RRBIs was found exclusively in females in the orbitofrontal regions, superior frontal gyrus, and intraparietal sulcus, while in males RRBIs tended to be associated with increased volume of the bilateral pallidum. Limitations: However, due to a small sample size and the small difference in RRBI symptoms within pairs, the results of this exploratory study need to be interpreted with caution. Conclusions: Our findings suggest that structural alterations of fronto-parietal networks in association with RRBIs are found mostly in females, while striatal networks are more affected in males. These results endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males. En ligne : http://dx.doi.org/10.1186/s13229-019-0309-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414

A comparative study of autistic and non-autistic women's experience of motherhood / A. L. POHL in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 3 p. Titre : A comparative study of autistic and non-autistic women's experience of motherhood Type de document : Texte imprimé et/ou numérique Auteurs : A. L. POHL, Auteur ; S. K. CROCKFORD, Auteur ; M. BLAKEMORE, Auteur ; Carrie ALLISON, Auteur ; Simon BARON-COHEN, Auteur Article en page(s) : 3 p. Langues : Anglais (eng) Mots-clés : Autism  Motherhood  Parenting Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism is a lifelong neurodevelopmental difference and disability, yet there is limited research examining parenting in autistic mothers. OBJECTIVE: To explore autistic mothers' experience of the perinatal period and parenthood. This includes pregnancy, childbirth, the postpartum period, self-perception of parenting strengths and weaknesses, communication with professionals in relation to one's child, mental health difficulties and the social experience of motherhood. It also includes disclosing one's diagnosis of autism in parenting contexts. METHODS: We used a community-based participatory research model, and recruited an advisory panel, with whom we co-developed an anonymous, online survey for autistic mothers. The online survey was completed by autistic and non-autistic mothers, and we compared their responses using Chi-squared analysis. SAMPLE: Autistic mothers (n = 355), and non-autistic mothers (n = 132), each of whom had at least one autistic child, were included in our final analysis. RESULTS: There were differences in education, gender identity and age of mother at birth of first child. Autistic mothers were more likely to have experienced additional psychiatric conditions, including pre- or post-partum depression, and reported greater difficulties in areas such as multi-tasking, coping with domestic responsibilities and creating social opportunities for their child. They were also more likely to report feeling misunderstood by professionals, and reported greater anxiety, higher rates of selective mutism, and not knowing which details were appropriate to share with professionals. They were also more likely to find motherhood an isolating experience, to worry about others judging their parenting, or feel unable to turn to others for support in parenting. However, despite these challenges, autistic mothers were able to act in the best interest of their child, putting their child's needs first. CONCLUSIONS: Autistic mothers face unique challenges and the stigma associated with autism may further exacerbate communication difficulties. Greater understanding and acceptance amongst individuals who interact with autistic mothers is needed, and autistic mothers would benefit from additional and better-tailored support. En ligne : http://dx.doi.org/10.1186/s13229-019-0304-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] A comparative study of autistic and non-autistic women's experience of motherhood [Texte imprimé et/ou numérique] / A. L. POHL, Auteur ; S. K. CROCKFORD, Auteur ; M. BLAKEMORE, Auteur ; Carrie ALLISON, Auteur ; Simon BARON-COHEN, Auteur . - 3 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 3 p. Mots-clés : Autism  Motherhood  Parenting Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism is a lifelong neurodevelopmental difference and disability, yet there is limited research examining parenting in autistic mothers. OBJECTIVE: To explore autistic mothers' experience of the perinatal period and parenthood. This includes pregnancy, childbirth, the postpartum period, self-perception of parenting strengths and weaknesses, communication with professionals in relation to one's child, mental health difficulties and the social experience of motherhood. It also includes disclosing one's diagnosis of autism in parenting contexts. METHODS: We used a community-based participatory research model, and recruited an advisory panel, with whom we co-developed an anonymous, online survey for autistic mothers. The online survey was completed by autistic and non-autistic mothers, and we compared their responses using Chi-squared analysis. SAMPLE: Autistic mothers (n = 355), and non-autistic mothers (n = 132), each of whom had at least one autistic child, were included in our final analysis. RESULTS: There were differences in education, gender identity and age of mother at birth of first child. Autistic mothers were more likely to have experienced additional psychiatric conditions, including pre- or post-partum depression, and reported greater difficulties in areas such as multi-tasking, coping with domestic responsibilities and creating social opportunities for their child. They were also more likely to report feeling misunderstood by professionals, and reported greater anxiety, higher rates of selective mutism, and not knowing which details were appropriate to share with professionals. They were also more likely to find motherhood an isolating experience, to worry about others judging their parenting, or feel unable to turn to others for support in parenting. However, despite these challenges, autistic mothers were able to act in the best interest of their child, putting their child's needs first. CONCLUSIONS: Autistic mothers face unique challenges and the stigma associated with autism may further exacerbate communication difficulties. Greater understanding and acceptance amongst individuals who interact with autistic mothers is needed, and autistic mothers would benefit from additional and better-tailored support. En ligne : http://dx.doi.org/10.1186/s13229-019-0304-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder / Nadja T. HOFER in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 4 p. Titre : Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder Type de document : Texte imprimé et/ou numérique Auteurs : Nadja T. HOFER, Auteur ; Petronel TULUC, Auteur ; Nadine J. ORTNER, Auteur ; Yuliia V. NIKONISHYNA, Auteur ; Monica L. FERNÁNDES-QUINTERO, Auteur ; Klaus R. LIEDL, Auteur ; Bernhard E. FLUCHER, Auteur ; Helen COX, Auteur ; Jörg STRIESSNIG, Auteur Article en page(s) : 4 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  cacna1d  Gain-of-function mutation  L-type Ca2+-channels  Neurodevelopmental disorder Index. décimale : PER Périodiques Résumé : BACKGROUND: There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3?L-type Ca(2+)-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely disease-causing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. METHODS: For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. RESULTS: Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~ 13-17?mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca(2+)-levels during action potential-like stimulations, characteristic for gain-of-function changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca(2+)-channel blocker isradipine by 3-4-fold.Conclusions and limitationsOur data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca(2+)-channel blockers. En ligne : http://dx.doi.org/10.1186/s13229-019-0310-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder [Texte imprimé et/ou numérique] / Nadja T. HOFER, Auteur ; Petronel TULUC, Auteur ; Nadine J. ORTNER, Auteur ; Yuliia V. NIKONISHYNA, Auteur ; Monica L. FERNÁNDES-QUINTERO, Auteur ; Klaus R. LIEDL, Auteur ; Bernhard E. FLUCHER, Auteur ; Helen COX, Auteur ; Jörg STRIESSNIG, Auteur . - 4 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 4 p. Mots-clés : Autism spectrum disorder  cacna1d  Gain-of-function mutation  L-type Ca2+-channels  Neurodevelopmental disorder Index. décimale : PER Périodiques Résumé : BACKGROUND: There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3?L-type Ca(2+)-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely disease-causing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. METHODS: For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. RESULTS: Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~ 13-17?mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca(2+)-levels during action potential-like stimulations, characteristic for gain-of-function changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca(2+)-channel blocker isradipine by 3-4-fold.Conclusions and limitationsOur data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca(2+)-channel blockers. En ligne : http://dx.doi.org/10.1186/s13229-019-0310-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling / Pauline MARTIN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 2 p. Titre : TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling Type de document : Texte imprimé et/ou numérique Auteurs : Pauline MARTIN, Auteur ; Vilas WAGH, Auteur ; Surya A. REIS, Auteur ; Serkan ERDIN, Auteur ; Roberta L. BEAUCHAMP, Auteur ; Ghalib SHAIKH, Auteur ; Michael E. TALKOWSKI, Auteur ; Elizabeth THIELE, Auteur ; Steven D. SHERIDAN, Auteur ; Stephen J. HAGGARTY, Auteur ; Vijaya RAMESH, Auteur Article en page(s) : 2 p. Langues : Anglais (eng) Mots-clés : CRISPR/Cas9  Disease modeling  Early neurodevelopment  Induced pluripotent stem cells  mek-erk1/2  MNK1/2-eIF4E  Neural progenitor cells  tsc1  Tuberous sclerosis complex  mTORC1  Therapeutics, Psy Therapeutics, and Souvien Therapeutics, none of who were involved  in this study. SDS is a scientific advisor for Outermost Therapeutics, Inc., which  played no part in the present study. The other authors declare no competing  interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. METHODS: Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. RESULTS: Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. CONCLUSION: MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD. En ligne : http://dx.doi.org/10.1186/s13229-019-0311-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling [Texte imprimé et/ou numérique] / Pauline MARTIN, Auteur ; Vilas WAGH, Auteur ; Surya A. REIS, Auteur ; Serkan ERDIN, Auteur ; Roberta L. BEAUCHAMP, Auteur ; Ghalib SHAIKH, Auteur ; Michael E. TALKOWSKI, Auteur ; Elizabeth THIELE, Auteur ; Steven D. SHERIDAN, Auteur ; Stephen J. HAGGARTY, Auteur ; Vijaya RAMESH, Auteur . - 2 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 2 p. Mots-clés : CRISPR/Cas9  Disease modeling  Early neurodevelopment  Induced pluripotent stem cells  mek-erk1/2  MNK1/2-eIF4E  Neural progenitor cells  tsc1  Tuberous sclerosis complex  mTORC1  Therapeutics, Psy Therapeutics, and Souvien Therapeutics, none of who were involved  in this study. SDS is a scientific advisor for Outermost Therapeutics, Inc., which  played no part in the present study. The other authors declare no competing  interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. METHODS: Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. RESULTS: Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. CONCLUSION: MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD. En ligne : http://dx.doi.org/10.1186/s13229-019-0311-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Children with autism spectrum disorder produce more ambiguous and less socially meaningful facial expressions: an experimental study using random forest classifiers / Charline GROSSARD in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 5 p. Titre : Children with autism spectrum disorder produce more ambiguous and less socially meaningful facial expressions: an experimental study using random forest classifiers Type de document : Texte imprimé et/ou numérique Auteurs : Charline GROSSARD, Auteur ; Arnaud DAPOGNY, Auteur ; David COHEN, Auteur ; Sacha BERNHEIM, Auteur ; Estelle JUILLET, Auteur ; Fanny HAMEL, Auteur ; Stéphanie HUN, Auteur ; Jérémy BOURGEOIS, Auteur ; Hugues PELLERIN, Auteur ; Sylvie SERRET, Auteur ; Kevin BAILLY, Auteur ; Laurence CHABY, Auteur Article en page(s) : 5 p. Langues : Anglais (eng) Mots-clés : Algorithm  Autism spectrum disorder  Emotion  Facial expressions Index. décimale : PER Périodiques Résumé : BACKGROUND: Computer vision combined with human annotation could offer a novel method for exploring facial expression (FE) dynamics in children with autism spectrum disorder (ASD). METHODS: We recruited 157 children with typical development (TD) and 36 children with ASD in Paris and Nice to perform two experimental tasks to produce FEs with emotional valence. FEs were explored by judging ratings and by random forest (RF) classifiers. To do so, we located a set of 49 facial landmarks in the task videos, we generated a set of geometric and appearance features and we used RF classifiers to explore how children with ASD differed from TD children when producing FEs. RESULTS: Using multivariate models including other factors known to predict FEs (age, gender, intellectual quotient, emotion subtype, cultural background), ratings from expert raters showed that children with ASD had more difficulty producing FEs than TD children. In addition, when we explored how RF classifiers performed, we found that classification tasks, except for those for sadness, were highly accurate and that RF classifiers needed more facial landmarks to achieve the best classification for children with ASD. Confusion matrices showed that when RF classifiers were tested in children with ASD, anger was often confounded with happiness. LIMITATIONS: The sample size of the group of children with ASD was lower than that of the group of TD children. By using several control calculations, we tried to compensate for this limitation. CONCLUSION: Children with ASD have more difficulty producing socially meaningful FEs. The computer vision methods we used to explore FE dynamics also highlight that the production of FEs in children with ASD carries more ambiguity. En ligne : http://dx.doi.org/10.1186/s13229-020-0312-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Children with autism spectrum disorder produce more ambiguous and less socially meaningful facial expressions: an experimental study using random forest classifiers [Texte imprimé et/ou numérique] / Charline GROSSARD, Auteur ; Arnaud DAPOGNY, Auteur ; David COHEN, Auteur ; Sacha BERNHEIM, Auteur ; Estelle JUILLET, Auteur ; Fanny HAMEL, Auteur ; Stéphanie HUN, Auteur ; Jérémy BOURGEOIS, Auteur ; Hugues PELLERIN, Auteur ; Sylvie SERRET, Auteur ; Kevin BAILLY, Auteur ; Laurence CHABY, Auteur . - 5 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 5 p. Mots-clés : Algorithm  Autism spectrum disorder  Emotion  Facial expressions Index. décimale : PER Périodiques Résumé : BACKGROUND: Computer vision combined with human annotation could offer a novel method for exploring facial expression (FE) dynamics in children with autism spectrum disorder (ASD). METHODS: We recruited 157 children with typical development (TD) and 36 children with ASD in Paris and Nice to perform two experimental tasks to produce FEs with emotional valence. FEs were explored by judging ratings and by random forest (RF) classifiers. To do so, we located a set of 49 facial landmarks in the task videos, we generated a set of geometric and appearance features and we used RF classifiers to explore how children with ASD differed from TD children when producing FEs. RESULTS: Using multivariate models including other factors known to predict FEs (age, gender, intellectual quotient, emotion subtype, cultural background), ratings from expert raters showed that children with ASD had more difficulty producing FEs than TD children. In addition, when we explored how RF classifiers performed, we found that classification tasks, except for those for sadness, were highly accurate and that RF classifiers needed more facial landmarks to achieve the best classification for children with ASD. Confusion matrices showed that when RF classifiers were tested in children with ASD, anger was often confounded with happiness. LIMITATIONS: The sample size of the group of children with ASD was lower than that of the group of TD children. By using several control calculations, we tried to compensate for this limitation. CONCLUSION: Children with ASD have more difficulty producing socially meaningful FEs. The computer vision methods we used to explore FE dynamics also highlight that the production of FEs in children with ASD carries more ambiguity. En ligne : http://dx.doi.org/10.1186/s13229-020-0312-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up / Sylvie BERNAERTS in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 6 p. Titre : Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up Type de document : Texte imprimé et/ou numérique Auteurs : Sylvie BERNAERTS, Auteur ; Bart BOETS, Auteur ; Guy BOSMANS, Auteur ; Jean STEYAERT, Auteur ; Kaat ALAERTS, Auteur Article en page(s) : 6 p. Langues : Anglais (eng) Mots-clés : Attachment  Autism spectrum disorder  Oxytocin  Repetitive and restricted behavior  Social responsiveness Index. décimale : PER Périodiques Résumé : BACKGROUND: Intranasal administration of the "prosocial" neuropeptide oxytocin is increasingly explored as a potential treatment for targeting the core characteristics of autism spectrum disorder (ASD). However, long-term follow-up studies, evaluating the possibility of long-lasting retention effects, are currently lacking. METHODS: Using a double-blind, randomized, placebo-controlled, parallel design, this pilot clinical trial explored the possibility of long-lasting behavioral effects of 4 weeks of intranasal oxytocin treatment (24 International Units once daily in the morning) in 40 adult men with ASD. To do so, self-report and informant-based questionnaires assessing core autism symptoms and characterizations of attachment were administered at baseline, immediately after 4 weeks of treatment (approximately 24 h after the last nasal spray administration), and at two follow-up sessions, 4 weeks and 1 year post-treatment. RESULTS: No treatment-specific effects were identified in the primary outcome assessing social symptoms (Social Responsiveness Scale, self- and informant-rated). In particular, with respect to self-reported social responsiveness, improvements were evident both in the oxytocin and in the placebo group, yielding no significant between-group difference (p = .37). Also informant-rated improvements in social responsiveness were not significantly larger in the oxytocin, compared to the placebo group (between-group difference: p = .19). Among the secondary outcome measures, treatment-specific improvements were identified in the Repetitive Behavior Scale and State Adult Attachment Measure, indicating reductions in self-reported repetitive behaviors (p = .04) and reduced feelings of avoidance toward others (p = .03) in the oxytocin group compared to the placebo group, up to 1 month and even 1 year post-treatment. Treatment-specific effects were also revealed in screenings of mood states (Profile of Mood States), indicating higher reports of "vigor" (feeling energetic, active, lively) in the oxytocin, compared to the placebo group (p = .03). CONCLUSIONS: While no treatment-specific improvements were evident in terms of core social symptoms, the current observations of long-term beneficial effects on repetitive behaviors and feelings of avoidance are promising and suggestive of a therapeutic potential of oxytocin treatment for ASD. However, given the exploratory nature of this pilot study, future studies are warranted to evaluate the long-term effects of OT administration further. TRIAL REGISTRATION: The trial was registered with the European Clinical Trial Registry (Eudract 2014-000586-45) on January 22, 2014 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000586-45/BE). En ligne : http://dx.doi.org/10.1186/s13229-020-0313-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up [Texte imprimé et/ou numérique] / Sylvie BERNAERTS, Auteur ; Bart BOETS, Auteur ; Guy BOSMANS, Auteur ; Jean STEYAERT, Auteur ; Kaat ALAERTS, Auteur . - 6 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 6 p. Mots-clés : Attachment  Autism spectrum disorder  Oxytocin  Repetitive and restricted behavior  Social responsiveness Index. décimale : PER Périodiques Résumé : BACKGROUND: Intranasal administration of the "prosocial" neuropeptide oxytocin is increasingly explored as a potential treatment for targeting the core characteristics of autism spectrum disorder (ASD). However, long-term follow-up studies, evaluating the possibility of long-lasting retention effects, are currently lacking. METHODS: Using a double-blind, randomized, placebo-controlled, parallel design, this pilot clinical trial explored the possibility of long-lasting behavioral effects of 4 weeks of intranasal oxytocin treatment (24 International Units once daily in the morning) in 40 adult men with ASD. To do so, self-report and informant-based questionnaires assessing core autism symptoms and characterizations of attachment were administered at baseline, immediately after 4 weeks of treatment (approximately 24 h after the last nasal spray administration), and at two follow-up sessions, 4 weeks and 1 year post-treatment. RESULTS: No treatment-specific effects were identified in the primary outcome assessing social symptoms (Social Responsiveness Scale, self- and informant-rated). In particular, with respect to self-reported social responsiveness, improvements were evident both in the oxytocin and in the placebo group, yielding no significant between-group difference (p = .37). Also informant-rated improvements in social responsiveness were not significantly larger in the oxytocin, compared to the placebo group (between-group difference: p = .19). Among the secondary outcome measures, treatment-specific improvements were identified in the Repetitive Behavior Scale and State Adult Attachment Measure, indicating reductions in self-reported repetitive behaviors (p = .04) and reduced feelings of avoidance toward others (p = .03) in the oxytocin group compared to the placebo group, up to 1 month and even 1 year post-treatment. Treatment-specific effects were also revealed in screenings of mood states (Profile of Mood States), indicating higher reports of "vigor" (feeling energetic, active, lively) in the oxytocin, compared to the placebo group (p = .03). CONCLUSIONS: While no treatment-specific improvements were evident in terms of core social symptoms, the current observations of long-term beneficial effects on repetitive behaviors and feelings of avoidance are promising and suggestive of a therapeutic potential of oxytocin treatment for ASD. However, given the exploratory nature of this pilot study, future studies are warranted to evaluate the long-term effects of OT administration further. TRIAL REGISTRATION: The trial was registered with the European Clinical Trial Registry (Eudract 2014-000586-45) on January 22, 2014 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000586-45/BE). En ligne : http://dx.doi.org/10.1186/s13229-020-0313-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Persistence and predictors of self-injurious behaviour in autism: a ten-year prospective cohort study / Catherine LAVERTY in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 8 p. Titre : Persistence and predictors of self-injurious behaviour in autism: a ten-year prospective cohort study Type de document : Texte imprimé et/ou numérique Auteurs : Catherine LAVERTY, Auteur ; Chris OLIVER, Auteur ; Jo MOSS, Auteur ; Lisa NELSON, Auteur ; Caroline RICHARDS, Auteur Article en page(s) : 8 p. Langues : Anglais (eng) Mots-clés : Autism  Impulsivity  Prevalence  Risk marker  Self-injury  Self-restraint Index. décimale : PER Périodiques Résumé : BACKGROUND: Self-injurious behaviours, such as head banging, hair pulling, skin picking and scratching, are common in individuals with autism. Despite high prevalence rates, there is a paucity of longitudinal research to refine models of risk and mechanism and inform service planning. In this longitudinal study, we investigated self-injury in a cohort of individuals with autism over 10?years to identify behavioural and demographic characteristics associated with persistent self-injury. METHODS: Carers of 67 individuals with autism completed questionnaires relating to the presence of self-injury and relevant risk markers at T (1) (mean [SD] age in years 13.4 [7.7]) and T (3) (mean [SD] age in years 23.9 [7.7]) 10?years later. Forty-six of these also took part at T (2) (3?years after initial participation). Analysis assessed demographic and behavioural risk markers for self-injury, as well as the predictive value of items assessed at T (1)and T (2.) RESULTS: Self-injury was persistent in 44% of individuals over the 10-year period, with behavioural characteristics of impulsivity (p < .001) and overactivity (p = .002), identified as risk markers for persistence. A predictive model of self-injury was derived from LASSO analysis, with baseline impulsivity, interest and pleasure, stereotyped behaviour, social communication and adaptive functioning predicting self-injury over 10?years. CONCLUSIONS: In this unique longitudinal investigation into the persistence of self-injury in a non-clinical sample of individuals with autism over a 10?year period, we have identified a novel, robust and stable profile of behavioural characteristics associated with persistent self-injury. Findings support an early intervention strategy targeted towards individuals identified to be at a higher risk of developing self-injurious behaviour. En ligne : http://dx.doi.org/10.1186/s13229-019-0307-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Persistence and predictors of self-injurious behaviour in autism: a ten-year prospective cohort study [Texte imprimé et/ou numérique] / Catherine LAVERTY, Auteur ; Chris OLIVER, Auteur ; Jo MOSS, Auteur ; Lisa NELSON, Auteur ; Caroline RICHARDS, Auteur . - 8 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 8 p. Mots-clés : Autism  Impulsivity  Prevalence  Risk marker  Self-injury  Self-restraint Index. décimale : PER Périodiques Résumé : BACKGROUND: Self-injurious behaviours, such as head banging, hair pulling, skin picking and scratching, are common in individuals with autism. Despite high prevalence rates, there is a paucity of longitudinal research to refine models of risk and mechanism and inform service planning. In this longitudinal study, we investigated self-injury in a cohort of individuals with autism over 10?years to identify behavioural and demographic characteristics associated with persistent self-injury. METHODS: Carers of 67 individuals with autism completed questionnaires relating to the presence of self-injury and relevant risk markers at T (1) (mean [SD] age in years 13.4 [7.7]) and T (3) (mean [SD] age in years 23.9 [7.7]) 10?years later. Forty-six of these also took part at T (2) (3?years after initial participation). Analysis assessed demographic and behavioural risk markers for self-injury, as well as the predictive value of items assessed at T (1)and T (2.) RESULTS: Self-injury was persistent in 44% of individuals over the 10-year period, with behavioural characteristics of impulsivity (p < .001) and overactivity (p = .002), identified as risk markers for persistence. A predictive model of self-injury was derived from LASSO analysis, with baseline impulsivity, interest and pleasure, stereotyped behaviour, social communication and adaptive functioning predicting self-injury over 10?years. CONCLUSIONS: In this unique longitudinal investigation into the persistence of self-injury in a non-clinical sample of individuals with autism over a 10?year period, we have identified a novel, robust and stable profile of behavioural characteristics associated with persistent self-injury. Findings support an early intervention strategy targeted towards individuals identified to be at a higher risk of developing self-injurious behaviour. En ligne : http://dx.doi.org/10.1186/s13229-019-0307-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Age-variant and age-invariant features of functional brain organization in middle-aged and older autistic adults / Joe BATHELT in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 9 p. Titre : Age-variant and age-invariant features of functional brain organization in middle-aged and older autistic adults Type de document : Texte imprimé et/ou numérique Auteurs : Joe BATHELT, Auteur ; P. Cédric KOOLSCHIJN, Auteur ; Hilde M. GEURTS, Auteur Article en page(s) : 9 p. Langues : Anglais (eng) Mots-clés : Aging  Autism spectrum disorder  Functional connectivity  Graph theory  perceived as posing a conflict or bias. The authors confirm that the funder had no  influence on the study design, preparation of the manuscript, or decision to  publish. Index. décimale : PER Périodiques Résumé : BACKGROUND: The majority of research effort into autism has been dedicated to understanding mechanisms during early development. As a consequence, research on the broader life course of an autism spectrum condition (ASC) has largely been neglected and almost nothing is known about ASC beyond middle age. Differences in brain connectivity that arise during early development may be maintained across the lifespan and may play protective or detrimental roles in older age. METHOD: This study explored age-related differences in functional connectivity across middle and older age in clinically diagnosed autistic adults (n?=?44, 30-73 years) and in an age-matched typical comparison group (n?=?45). RESULTS: The results indicated parallel age-related associations in ASC and typical aging for the local efficiency and connection strength of the default mode network and for the segregation of the frontoparietal control network. In contrast, group differences in visual network connectivity are compatible with a safeguarding interpretation of less age-related decline in brain function in ASC. This divergence was mirrored in different associations between visual network connectivity and reaction time variability in the ASC and comparison group. LIMITATIONS: The study is cross-sectional and may be affected by cohort effects. As all participants received their autism diagnosis in adulthood, this might hinder generalizability. CONCLUSION: These results highlight the complexity of aging in ASC with both parallel and divergent trajectories across different aspects of functional network organization. En ligne : http://dx.doi.org/10.1186/s13229-020-0316-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Age-variant and age-invariant features of functional brain organization in middle-aged and older autistic adults [Texte imprimé et/ou numérique] / Joe BATHELT, Auteur ; P. Cédric KOOLSCHIJN, Auteur ; Hilde M. GEURTS, Auteur . - 9 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 9 p. Mots-clés : Aging  Autism spectrum disorder  Functional connectivity  Graph theory  perceived as posing a conflict or bias. The authors confirm that the funder had no  influence on the study design, preparation of the manuscript, or decision to  publish. Index. décimale : PER Périodiques Résumé : BACKGROUND: The majority of research effort into autism has been dedicated to understanding mechanisms during early development. As a consequence, research on the broader life course of an autism spectrum condition (ASC) has largely been neglected and almost nothing is known about ASC beyond middle age. Differences in brain connectivity that arise during early development may be maintained across the lifespan and may play protective or detrimental roles in older age. METHOD: This study explored age-related differences in functional connectivity across middle and older age in clinically diagnosed autistic adults (n?=?44, 30-73 years) and in an age-matched typical comparison group (n?=?45). RESULTS: The results indicated parallel age-related associations in ASC and typical aging for the local efficiency and connection strength of the default mode network and for the segregation of the frontoparietal control network. In contrast, group differences in visual network connectivity are compatible with a safeguarding interpretation of less age-related decline in brain function in ASC. This divergence was mirrored in different associations between visual network connectivity and reaction time variability in the ASC and comparison group. LIMITATIONS: The study is cross-sectional and may be affected by cohort effects. As all participants received their autism diagnosis in adulthood, this might hinder generalizability. CONCLUSION: These results highlight the complexity of aging in ASC with both parallel and divergent trajectories across different aspects of functional network organization. En ligne : http://dx.doi.org/10.1186/s13229-020-0316-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD) / Federica FILICE in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 10 p. Titre : Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD) Type de document : Texte imprimé et/ou numérique Auteurs : Federica FILICE, Auteur ; Beat SCHWALLER, Auteur ; Tanja M. MICHEL, Auteur ; Edna GRÜNBLATT, Auteur Article en page(s) : 10 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  CRISPR-Cas9 technology  GABAergic  Induced pluripotent stem cells  Interneuron  Parvalbumin  Schizophrenia Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are persistent conditions resulting from disrupted/altered neurodevelopment. ASD multifactorial etiology-and its numerous comorbid conditions-heightens the difficulty in identifying its underlying causes, thus obstructing the development of effective therapies. Increasing evidence from both animal and human studies suggests an altered functioning of the parvalbumin (PV)-expressing inhibitory interneurons as a common and possibly unifying pathway for some forms of ASD. PV-expressing interneurons (short: PVALB neurons) are critically implicated in the regulation of cortical networks' activity. Their particular connectivity patterns, i.e., their preferential targeting of perisomatic regions and axon initial segments of pyramidal cells, as well as their reciprocal connections, enable PVALB neurons to exert a fine-tuned control of, e.g., spike timing, resulting in the generation and modulation of rhythms in the gamma range, which are important for sensory perception and attention.New methodologies such as induced pluripotent stem cells (iPSC) and genome-editing techniques (CRISPR/Cas9) have proven to be valuable tools to get mechanistic insight in neurodevelopmental and/or neurodegenerative and neuropsychiatric diseases. Such technological advances have enabled the generation of PVALB neurons from iPSC. Tagging of these neurons would allow following their fate during the development, from precursor cells to differentiated (and functional) PVALB neurons. Also, it would enable a better understanding of PVALB neuron function, using either iPSC from healthy donors or ASD patients with known mutations in ASD risk genes. In this concept paper, the strategies hopefully leading to a better understanding of PVALB neuron function(s) are briefly discussed. We envision that such an iPSC-based approach combined with emerging (genetic) technologies may offer the opportunity to investigate in detail the role of PVALB neurons and PV during "neurodevelopment ex vivo." En ligne : http://dx.doi.org/10.1186/s13229-020-0314-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD) [Texte imprimé et/ou numérique] / Federica FILICE, Auteur ; Beat SCHWALLER, Auteur ; Tanja M. MICHEL, Auteur ; Edna GRÜNBLATT, Auteur . - 10 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 10 p. Mots-clés : Autism spectrum disorder  CRISPR-Cas9 technology  GABAergic  Induced pluripotent stem cells  Interneuron  Parvalbumin  Schizophrenia Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are persistent conditions resulting from disrupted/altered neurodevelopment. ASD multifactorial etiology-and its numerous comorbid conditions-heightens the difficulty in identifying its underlying causes, thus obstructing the development of effective therapies. Increasing evidence from both animal and human studies suggests an altered functioning of the parvalbumin (PV)-expressing inhibitory interneurons as a common and possibly unifying pathway for some forms of ASD. PV-expressing interneurons (short: PVALB neurons) are critically implicated in the regulation of cortical networks' activity. Their particular connectivity patterns, i.e., their preferential targeting of perisomatic regions and axon initial segments of pyramidal cells, as well as their reciprocal connections, enable PVALB neurons to exert a fine-tuned control of, e.g., spike timing, resulting in the generation and modulation of rhythms in the gamma range, which are important for sensory perception and attention.New methodologies such as induced pluripotent stem cells (iPSC) and genome-editing techniques (CRISPR/Cas9) have proven to be valuable tools to get mechanistic insight in neurodevelopmental and/or neurodegenerative and neuropsychiatric diseases. Such technological advances have enabled the generation of PVALB neurons from iPSC. Tagging of these neurons would allow following their fate during the development, from precursor cells to differentiated (and functional) PVALB neurons. Also, it would enable a better understanding of PVALB neuron function, using either iPSC from healthy donors or ASD patients with known mutations in ASD risk genes. In this concept paper, the strategies hopefully leading to a better understanding of PVALB neuron function(s) are briefly discussed. We envision that such an iPSC-based approach combined with emerging (genetic) technologies may offer the opportunity to investigate in detail the role of PVALB neurons and PV during "neurodevelopment ex vivo." En ligne : http://dx.doi.org/10.1186/s13229-020-0314-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Reduced nonverbal interpersonal synchrony in autism spectrum disorder independent of partner diagnosis: a motion energy study / Alexandra Livia GEORGESCU in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 11 p. Titre : Reduced nonverbal interpersonal synchrony in autism spectrum disorder independent of partner diagnosis: a motion energy study Type de document : Texte imprimé et/ou numérique Auteurs : Alexandra Livia GEORGESCU, Auteur ; S. KOEROGLU, Auteur ; Antonia HAMILTON, Auteur ; Kai VOGELEY, Auteur ; C. M. FALTER-WAGNER, Auteur ; W. TSCHACHER, Auteur Article en page(s) : 11 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Autism spectrum disorders  Conversation  Dyadic interactions  Interactional heterogeneity  Interpersonal coordination  Interpersonal synchrony  Motion energy  Motion energy analysis  Nonverbal behaviour  Social interaction Index. décimale : PER Périodiques Résumé : BACKGROUND: One of the main diagnostic features of individuals with autism spectrum disorders is nonverbal behaviour difficulties during naturalistic social interactions. The 'Interactional Heterogeneity Hypothesis' of ASD proposes that the degree to which individuals share a common ground substantially influences their ability to achieve smooth social interactions. METHODS: To test this hypothesis, we filmed 29 autistic and 29 matched typically developed adults engaged in several conversational tasks. Windowed cross-lagged correlations were computed using the time series of motion energy of both individuals in a dyad. These coefficients were then compared across the three dyad types that were homo- or heterogenous with respect to diagnosis: pairs of two autistic individuals, two typically developed individuals or pairs of one autistic and one typically developed person. RESULTS: We found that all dyad types achieved above-chance interpersonal synchrony, but that synchrony was more expressed in typical dyads compared to both autistic and mixed dyads. LIMITATIONS: The method presented here provides only one, albeit objective and robust, approach to explore synchrony. The methodological choices as well as the lack of consideration for other communication modalities may limit our interpretation of the findings. Moreover, the sample size is small with respect to exploring associations between synchrony and various outcome and social skill measures. CONCLUSIONS: The present results do not provide support for the Interactional Heterogeneity Hypothesis given that autistic individuals do not coordinate better when interacting with another autistic individual, compared to when interacting with a typical individual. En ligne : http://dx.doi.org/10.1186/s13229-019-0305-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Reduced nonverbal interpersonal synchrony in autism spectrum disorder independent of partner diagnosis: a motion energy study [Texte imprimé et/ou numérique] / Alexandra Livia GEORGESCU, Auteur ; S. KOEROGLU, Auteur ; Antonia HAMILTON, Auteur ; Kai VOGELEY, Auteur ; C. M. FALTER-WAGNER, Auteur ; W. TSCHACHER, Auteur . - 11 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 11 p. Mots-clés : Autism spectrum disorder  Autism spectrum disorders  Conversation  Dyadic interactions  Interactional heterogeneity  Interpersonal coordination  Interpersonal synchrony  Motion energy  Motion energy analysis  Nonverbal behaviour  Social interaction Index. décimale : PER Périodiques Résumé : BACKGROUND: One of the main diagnostic features of individuals with autism spectrum disorders is nonverbal behaviour difficulties during naturalistic social interactions. The 'Interactional Heterogeneity Hypothesis' of ASD proposes that the degree to which individuals share a common ground substantially influences their ability to achieve smooth social interactions. METHODS: To test this hypothesis, we filmed 29 autistic and 29 matched typically developed adults engaged in several conversational tasks. Windowed cross-lagged correlations were computed using the time series of motion energy of both individuals in a dyad. These coefficients were then compared across the three dyad types that were homo- or heterogenous with respect to diagnosis: pairs of two autistic individuals, two typically developed individuals or pairs of one autistic and one typically developed person. RESULTS: We found that all dyad types achieved above-chance interpersonal synchrony, but that synchrony was more expressed in typical dyads compared to both autistic and mixed dyads. LIMITATIONS: The method presented here provides only one, albeit objective and robust, approach to explore synchrony. The methodological choices as well as the lack of consideration for other communication modalities may limit our interpretation of the findings. Moreover, the sample size is small with respect to exploring associations between synchrony and various outcome and social skill measures. CONCLUSIONS: The present results do not provide support for the Interactional Heterogeneity Hypothesis given that autistic individuals do not coordinate better when interacting with another autistic individual, compared to when interacting with a typical individual. En ligne : http://dx.doi.org/10.1186/s13229-019-0305-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Serotonergic innervation of the amygdala is increased in autism spectrum disorder and decreased in Williams syndrome / C. H. LEW in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 12 p. Titre : Serotonergic innervation of the amygdala is increased in autism spectrum disorder and decreased in Williams syndrome Type de document : Texte imprimé et/ou numérique Auteurs : C. H. LEW, Auteur ; K. M. GROENIGER, Auteur ; K. L. HANSON, Auteur ; D. CUEVAS, Auteur ; D. M. Z. GREINER, Auteur ; B. HRVOJ-MIHIC, Auteur ; Ursula BELLUGI, Auteur ; C. M. SCHUMANN, Auteur ; K. SEMENDEFERI, Auteur Article en page(s) : 12 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Williams syndrome (WS) and autism spectrum disorder (ASD) are neurodevelopmental disorders that demonstrate overlapping genetic associations, dichotomous sociobehavioral phenotypes, and dichotomous pathological differences in neuronal distribution in key social brain areas, including the prefrontal cortex and the amygdala. The serotonergic system is critical to many processes underlying neurodevelopment and is additionally an important neuromodulator associated with behavioral variation. The amygdala is heavily innervated by serotonergic projections, suggesting that the serotonergic system is a significant mediator of neuronal activity. Disruptions to the serotonergic system, and atypical structure and function of the amygdala, are implicated in both WS and ASD. METHODS: We quantified the serotonergic axon density in the four major subdivisions of the amygdala in the postmortem brains of individuals diagnosed with ASD and WS and neurotypical (NT) brains. RESULTS: We found opposing directions of change in serotonergic innervation in the two disorders, with ASD displaying an increase in serotonergic axons compared to NT and WS displaying a decrease. Significant differences (p? En ligne : http://dx.doi.org/10.1186/s13229-019-0302-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Serotonergic innervation of the amygdala is increased in autism spectrum disorder and decreased in Williams syndrome [Texte imprimé et/ou numérique] / C. H. LEW, Auteur ; K. M. GROENIGER, Auteur ; K. L. HANSON, Auteur ; D. CUEVAS, Auteur ; D. M. Z. GREINER, Auteur ; B. HRVOJ-MIHIC, Auteur ; Ursula BELLUGI, Auteur ; C. M. SCHUMANN, Auteur ; K. SEMENDEFERI, Auteur . - 12 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 12 p. Index. décimale : PER Périodiques Résumé : BACKGROUND: Williams syndrome (WS) and autism spectrum disorder (ASD) are neurodevelopmental disorders that demonstrate overlapping genetic associations, dichotomous sociobehavioral phenotypes, and dichotomous pathological differences in neuronal distribution in key social brain areas, including the prefrontal cortex and the amygdala. The serotonergic system is critical to many processes underlying neurodevelopment and is additionally an important neuromodulator associated with behavioral variation. The amygdala is heavily innervated by serotonergic projections, suggesting that the serotonergic system is a significant mediator of neuronal activity. Disruptions to the serotonergic system, and atypical structure and function of the amygdala, are implicated in both WS and ASD. METHODS: We quantified the serotonergic axon density in the four major subdivisions of the amygdala in the postmortem brains of individuals diagnosed with ASD and WS and neurotypical (NT) brains. RESULTS: We found opposing directions of change in serotonergic innervation in the two disorders, with ASD displaying an increase in serotonergic axons compared to NT and WS displaying a decrease. Significant differences (p? En ligne : http://dx.doi.org/10.1186/s13229-019-0302-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Transcriptomics of Gabra4 knockout mice reveals common NMDAR pathways underlying autism, memory, and epilepsy / Cuixia FAN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 13 p. Titre : Transcriptomics of Gabra4 knockout mice reveals common NMDAR pathways underlying autism, memory, and epilepsy Type de document : Texte imprimé et/ou numérique Auteurs : Cuixia FAN, Auteur ; Yue GAO, Auteur ; Guanmei LIANG, Auteur ; Lang HUANG, Auteur ; Jing WANG, Auteur ; Xiaoxue YANG, Auteur ; Yiwu SHI, Auteur ; Ursula C DRÄGER, Auteur ; Mei ZHONG, Auteur ; Tian-Ming GAO, Auteur ; Xinping YANG, Auteur Article en page(s) : 13 p. Langues : Anglais (eng) Mots-clés : Autism  Epilepsy  Gabra4  Interactome  NMDARs  Transcriptome Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neuronal developmental disorder with impaired social interaction and communication, often with abnormal intelligence and comorbidity with epilepsy. Disturbances in synaptic transmission, including the GABAergic, glutamatergic, and serotonergic systems, are known to be involved in the pathogenesis of this disorder, yet we do not know if there is a common molecular mechanism. As mutations in the GABAergic receptor subunit gene GABRA4 are reported in patients with ASD, we eliminated the Gabra4 gene in mice and found that the Gabra4 knockout mice showed autistic-like behavior, enhanced spatial memory, and attenuated susceptibility to pentylenetetrazol-induced seizures, a constellation of symptoms resembling human high-functioning autism. To search for potential molecular pathways involved in these phenotypes, we performed a hippocampal transcriptome profiling, constructed a hippocampal interactome network, and revealed an upregulation of the NMDAR system at the center of the converged pathways underlying high-functioning autism-like and anti-epilepsy phenotypes. En ligne : http://dx.doi.org/10.1186/s13229-020-0318-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Transcriptomics of Gabra4 knockout mice reveals common NMDAR pathways underlying autism, memory, and epilepsy [Texte imprimé et/ou numérique] / Cuixia FAN, Auteur ; Yue GAO, Auteur ; Guanmei LIANG, Auteur ; Lang HUANG, Auteur ; Jing WANG, Auteur ; Xiaoxue YANG, Auteur ; Yiwu SHI, Auteur ; Ursula C DRÄGER, Auteur ; Mei ZHONG, Auteur ; Tian-Ming GAO, Auteur ; Xinping YANG, Auteur . - 13 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 13 p. Mots-clés : Autism  Epilepsy  Gabra4  Interactome  NMDARs  Transcriptome Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neuronal developmental disorder with impaired social interaction and communication, often with abnormal intelligence and comorbidity with epilepsy. Disturbances in synaptic transmission, including the GABAergic, glutamatergic, and serotonergic systems, are known to be involved in the pathogenesis of this disorder, yet we do not know if there is a common molecular mechanism. As mutations in the GABAergic receptor subunit gene GABRA4 are reported in patients with ASD, we eliminated the Gabra4 gene in mice and found that the Gabra4 knockout mice showed autistic-like behavior, enhanced spatial memory, and attenuated susceptibility to pentylenetetrazol-induced seizures, a constellation of symptoms resembling human high-functioning autism. To search for potential molecular pathways involved in these phenotypes, we performed a hippocampal transcriptome profiling, constructed a hippocampal interactome network, and revealed an upregulation of the NMDAR system at the center of the converged pathways underlying high-functioning autism-like and anti-epilepsy phenotypes. En ligne : http://dx.doi.org/10.1186/s13229-020-0318-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Links between self-injury and suicidality in autism / R. L. MOSELEY in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 14 p. Titre : Links between self-injury and suicidality in autism Type de document : Texte imprimé et/ou numérique Auteurs : R. L. MOSELEY, Auteur ; N. J. GREGORY, Auteur ; P. SMITH, Auteur ; Carrie ALLISON, Auteur ; Simon BARON-COHEN, Auteur Article en page(s) : 14 p. Langues : Anglais (eng) Mots-clés : Autism  Self-injury  Suicidality Index. décimale : PER Périodiques Résumé : BACKGROUND: Autistic individuals without intellectual disability are at heightened risk of self-injury, and appear to engage in it for similar reasons as non-autistic people. A wide divergence of autistic perspectives on self-injury, including those who frame it as a helpful coping mechanism, motivate investigating the link between self-injury, suicide ideation, and attempts which has been reported in typically developing individuals. METHOD: One hundred three autistic participants completed the Non-Suicidal Self-Injury Assessment Tool (NSSI-AT), the Suicide Behaviors Questionnaire (SBQ-R), and the Interpersonal Social Evaluation List (ISEL-12) across two online studies. Logistic regression was conducted to predict self-harming status via responses to questions on suicidality, and to predict whether certain self-injurious behaviors, including cutting, were especially associated with suicide ideation and attempts. Non-parametric correlation analysis examined relationships between suicide ideation/attempts and other variables that might characterize self-harmers especially at risk of suicidality. These included perceived access to social support, purposes or reasons for self-injury, the number of different self-injurious behaviors engaged in, the duration and lifetime incidence of self-injury, and the individual's feelings about their self-injury. RESULTS: While self-injuring status was significantly predicted by responses to a question on suicide ideation and attempts, there was no relationship between suicide ideation/attempts and a participant's personal feelings about their self-injury. The method of cutting was also predicted by suicide ideation and attempts, though other methods common in autistic people were at borderline significance. Use of self-injury for the regulation of low-energy emotional states like depression, for self-punishment or deterrence from suicide, and for sensory stimulation, was associated with suicide ideation and attempts, as was the number of self-injurious behaviors engaged in. There was no significant relationship between suicide ideation/attempts and the duration and lifetime incidence of self-injury or social support. CONCLUSIONS: These preliminary data suggest that while individuals might frame their self-injury as a positive or neutral thing, there remains a concerning relationship between self-injury and suicidality which exists regardless of individual feelings on self-injury. This is consistent with the theoretical perspective that self-injury can be a "gateway" through which individuals acquire capability for lethal suicidal behaviors. The data highlight that particular methods (cutting) and reasons for self-injury may be of significant concern, but this information, which might be of extreme value for clinicians, requires further investigation and validation. En ligne : http://dx.doi.org/10.1186/s13229-020-0319-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Links between self-injury and suicidality in autism [Texte imprimé et/ou numérique] / R. L. MOSELEY, Auteur ; N. J. GREGORY, Auteur ; P. SMITH, Auteur ; Carrie ALLISON, Auteur ; Simon BARON-COHEN, Auteur . - 14 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 14 p. Mots-clés : Autism  Self-injury  Suicidality Index. décimale : PER Périodiques Résumé : BACKGROUND: Autistic individuals without intellectual disability are at heightened risk of self-injury, and appear to engage in it for similar reasons as non-autistic people. A wide divergence of autistic perspectives on self-injury, including those who frame it as a helpful coping mechanism, motivate investigating the link between self-injury, suicide ideation, and attempts which has been reported in typically developing individuals. METHOD: One hundred three autistic participants completed the Non-Suicidal Self-Injury Assessment Tool (NSSI-AT), the Suicide Behaviors Questionnaire (SBQ-R), and the Interpersonal Social Evaluation List (ISEL-12) across two online studies. Logistic regression was conducted to predict self-harming status via responses to questions on suicidality, and to predict whether certain self-injurious behaviors, including cutting, were especially associated with suicide ideation and attempts. Non-parametric correlation analysis examined relationships between suicide ideation/attempts and other variables that might characterize self-harmers especially at risk of suicidality. These included perceived access to social support, purposes or reasons for self-injury, the number of different self-injurious behaviors engaged in, the duration and lifetime incidence of self-injury, and the individual's feelings about their self-injury. RESULTS: While self-injuring status was significantly predicted by responses to a question on suicide ideation and attempts, there was no relationship between suicide ideation/attempts and a participant's personal feelings about their self-injury. The method of cutting was also predicted by suicide ideation and attempts, though other methods common in autistic people were at borderline significance. Use of self-injury for the regulation of low-energy emotional states like depression, for self-punishment or deterrence from suicide, and for sensory stimulation, was associated with suicide ideation and attempts, as was the number of self-injurious behaviors engaged in. There was no significant relationship between suicide ideation/attempts and the duration and lifetime incidence of self-injury or social support. CONCLUSIONS: These preliminary data suggest that while individuals might frame their self-injury as a positive or neutral thing, there remains a concerning relationship between self-injury and suicidality which exists regardless of individual feelings on self-injury. This is consistent with the theoretical perspective that self-injury can be a "gateway" through which individuals acquire capability for lethal suicidal behaviors. The data highlight that particular methods (cutting) and reasons for self-injury may be of significant concern, but this information, which might be of extreme value for clinicians, requires further investigation and validation. En ligne : http://dx.doi.org/10.1186/s13229-020-0319-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Quantifying compensatory strategies in adults with and without diagnosed autism / Lucy Anne LIVINGSTON in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 15 p. Titre : Quantifying compensatory strategies in adults with and without diagnosed autism Type de document : Texte imprimé et/ou numérique Auteurs : Lucy Anne LIVINGSTON, Auteur ; Punit SHAH, Auteur ; Victoria MILNER, Auteur ; Francesca HAPPE, Auteur Article en page(s) : 15 p. Langues : Anglais (eng) Mots-clés : Adaptation  Autism  Camouflaging  Compensation  Compensatory strategies  Social cognition Index. décimale : PER Périodiques Résumé : BACKGROUND: There is growing recognition that some autistic people engage in 'compensation', showing few behavioural symptoms (e.g. neurotypical social skills), despite continuing to experience autism-related cognitive difficulties (e.g. difficulties in social cognition). One way this might be achieved is by individuals consciously employing 'compensatory strategies' during everyday social interaction. However, very little is currently known about the broad range of these strategies, their mechanisms and consequences for clinical presentation and diagnosis. METHODS: We aimed to measure compensatory strategies in autism for the first time. Using a novel checklist, we quantified self-reported social compensatory strategies in 117 adults (58 with autism, 59 without autism) and explored the relationships between compensation scores and autism diagnostic status, autistic traits, education level, sex and age at diagnosis. RESULTS: Higher compensation scores-representing a greater repertoire of compensatory strategies-were associated with having an autism diagnosis, more autistic traits and a higher education level. The link between autism diagnostic status and compensation scores was, however, explained by autistic traits and education level. Compensation scores were unrelated to sex or age at diagnosis. LIMITATIONS: Our sample was self-selected and predominantly comprised of intellectually able females; therefore, our findings may not generalise to the wider autistic population. CONCLUSIONS: Together, our findings suggest that many intellectually able adults, with and without a clinical diagnosis of autism, report using compensatory strategies to modify their social behaviour. We discuss the clinical utility of measuring self-reported compensation (e.g., using our checklist), with important implications for the accurate diagnosis and management of autism and related conditions. En ligne : http://dx.doi.org/10.1186/s13229-019-0308-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Quantifying compensatory strategies in adults with and without diagnosed autism [Texte imprimé et/ou numérique] / Lucy Anne LIVINGSTON, Auteur ; Punit SHAH, Auteur ; Victoria MILNER, Auteur ; Francesca HAPPE, Auteur . - 15 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 15 p. Mots-clés : Adaptation  Autism  Camouflaging  Compensation  Compensatory strategies  Social cognition Index. décimale : PER Périodiques Résumé : BACKGROUND: There is growing recognition that some autistic people engage in 'compensation', showing few behavioural symptoms (e.g. neurotypical social skills), despite continuing to experience autism-related cognitive difficulties (e.g. difficulties in social cognition). One way this might be achieved is by individuals consciously employing 'compensatory strategies' during everyday social interaction. However, very little is currently known about the broad range of these strategies, their mechanisms and consequences for clinical presentation and diagnosis. METHODS: We aimed to measure compensatory strategies in autism for the first time. Using a novel checklist, we quantified self-reported social compensatory strategies in 117 adults (58 with autism, 59 without autism) and explored the relationships between compensation scores and autism diagnostic status, autistic traits, education level, sex and age at diagnosis. RESULTS: Higher compensation scores-representing a greater repertoire of compensatory strategies-were associated with having an autism diagnosis, more autistic traits and a higher education level. The link between autism diagnostic status and compensation scores was, however, explained by autistic traits and education level. Compensation scores were unrelated to sex or age at diagnosis. LIMITATIONS: Our sample was self-selected and predominantly comprised of intellectually able females; therefore, our findings may not generalise to the wider autistic population. CONCLUSIONS: Together, our findings suggest that many intellectually able adults, with and without a clinical diagnosis of autism, report using compensatory strategies to modify their social behaviour. We discuss the clinical utility of measuring self-reported compensation (e.g., using our checklist), with important implications for the accurate diagnosis and management of autism and related conditions. En ligne : http://dx.doi.org/10.1186/s13229-019-0308-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex / Wardiya AFSHAR SABER in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 16 p. Titre : Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex Type de document : Texte imprimé et/ou numérique Auteurs : Wardiya AFSHAR SABER, Auteur ; Mustafa SAHIN, Auteur Article en page(s) : 16 p. Langues : Anglais (eng) Mots-clés : Astrocytes  Autism  Brain organoids  CRISPR/Cas9  Cortical tuber  Human pluripotent stem cells  Neurons  Purkinje neurons  Tuberous sclerosis complex  Therapeutics, and Quadrant Biosciences and has served on the Scientific Advisory  Board of Sage Therapeutics, Roche, Takeda, and PTEN Research Foundation. Index. décimale : PER Périodiques Résumé : Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, intellectual disability, and benign tumors of the brain, heart, skin, and kidney. Animal models have contributed to our understanding of normal and abnormal human brain development, but the construction of models that accurately recapitulate a human pathology remains challenging. Recent advances in stem cell biology with the derivation of human-induced pluripotent stem cells (hiPSCs) from somatic cells from patients have opened new avenues to the study of TSC. This approach combined with gene-editing tools such as CRISPR/Cas9 offers the advantage of preserving patient-specific genetic background and the ability to generate isogenic controls by correcting a specific mutation. The patient cell line and the isogenic control can be differentiated into the cell type of interest to model various aspects of TSC. In this review, we discuss the remarkable capacity of these cells to be used as a model for TSC in two- and three-dimensional cultures, the potential variability in iPSC models, and highlight differences between findings reported to date. En ligne : http://dx.doi.org/10.1186/s13229-020-0320-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex [Texte imprimé et/ou numérique] / Wardiya AFSHAR SABER, Auteur ; Mustafa SAHIN, Auteur . - 16 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 16 p. Mots-clés : Astrocytes  Autism  Brain organoids  CRISPR/Cas9  Cortical tuber  Human pluripotent stem cells  Neurons  Purkinje neurons  Tuberous sclerosis complex  Therapeutics, and Quadrant Biosciences and has served on the Scientific Advisory  Board of Sage Therapeutics, Roche, Takeda, and PTEN Research Foundation. Index. décimale : PER Périodiques Résumé : Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, intellectual disability, and benign tumors of the brain, heart, skin, and kidney. Animal models have contributed to our understanding of normal and abnormal human brain development, but the construction of models that accurately recapitulate a human pathology remains challenging. Recent advances in stem cell biology with the derivation of human-induced pluripotent stem cells (hiPSCs) from somatic cells from patients have opened new avenues to the study of TSC. This approach combined with gene-editing tools such as CRISPR/Cas9 offers the advantage of preserving patient-specific genetic background and the ability to generate isogenic controls by correcting a specific mutation. The patient cell line and the isogenic control can be differentiated into the cell type of interest to model various aspects of TSC. In this review, we discuss the remarkable capacity of these cells to be used as a model for TSC in two- and three-dimensional cultures, the potential variability in iPSC models, and highlight differences between findings reported to date. En ligne : http://dx.doi.org/10.1186/s13229-020-0320-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Social brain activation during mentalizing in a large autism cohort: the Longitudinal European Autism Project / Carolin MOESSNANG in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 17 p. Titre : Social brain activation during mentalizing in a large autism cohort: the Longitudinal European Autism Project Type de document : Texte imprimé et/ou numérique Auteurs : Carolin MOESSNANG, Auteur ; Sarah BAUMEISTER, Auteur ; Julian TILLMANN, Auteur ; David GOYARD, Auteur ; Tony CHARMAN, Auteur ; Sara AMBROSINO, Auteur ; Simon BARON-COHEN, Auteur ; Christian F. BECKMANN, Auteur ; Sven BÖLTE, Auteur ; Carsten BOURS, Auteur ; Daisy CRAWLEY, Auteur ; Flavio DELL'ACQUA, Auteur ; Sarah DURSTON, Auteur ; Christine ECKER, Auteur ; Vincent FROUIN, Auteur ; Hannah HAYWARD, Auteur ; Rosemary HOLT, Auteur ; Mark H. JOHNSON, Auteur ; Emily JONES, Auteur ; Meng-Chuan LAI, Auteur ; Michael V. LOMBARDO, Auteur ; Luke MASON, Auteur ; Marianne OLDENHINKEL, Auteur ; Antonio PERSICO, Auteur ; Antonia SAN JOSE CACERES, Auteur ; Will SPOOREN, Auteur ; Eva LOTH, Auteur ; Declan G. M. MURPHY, Auteur ; Jan K. BUITELAAR, Auteur ; Tobias BANASCHEWSKI, Auteur ; Daniel BRANDEIS, Auteur ; Heike TOST, Auteur ; Andreas MEYER-LINDENBERG, Auteur Article en page(s) : 17 p. Langues : Anglais (eng) Mots-clés : Animated shapes  Autism  Autism spectrum disorder  Development  Mentalizing  Multi-site  Social brain  Theory of mind  fMRI  Science, Atheneum Partners, Blueprint Partnership, Boehringer Ingelheim, Daimler und  Benz Stiftung, Elsevier, F. Hoffmann-La Roche, ICARE Schizophrenia, K. G. Jebsen  Foundation, L.E.K Consulting, Lundbeck International Foundation (LINF), R. Adamczak,  Roche Pharma, Science Foundation, Sumitomo Dainippon Pharma, Synapsis  Foundation–Alzheimer Research Switzerland, and System Analytics, and has received  lectures fees including travel fees from Boehringer Ingelheim, Fama Public  Relations, Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),  Janssen-Cilag, Klinikum Christophsbad, Göppingen, Lilly Deutschland, Luzerner  Psychiatrie, LVR Klinikum Düsseldorf, LWL Psychiatrie Verbund Westfalen-Lippe,  Otsuka Pharmaceuticals, Reunions i Ciencia S. L., Spanish Society of Psychiatry,  Südwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. WM has received  lecture or travel fees from Pfizer, Grünenthal, University of Zürich, International  Association for the Study on Pain (IASP), and European Federation of IASP Chapters  (EFIC). SB discloses that he has in the last 5?years acted as an author, consultant  or lecturer for Shire, Medice, Roche, Eli Lilly, Prima Psychiatry, GLGroup, System  Analytic, Ability Partner, Kompetento, Expo Medica, Clarion Healthcare, and  Prophase. He receives royalties for textbooks and diagnostic tools from  Huber/Hogrefe, Kohlhammer, and UTB. The other authors declare that they have no  competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the "social brain," a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD. METHODS: As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N = 205) and typically developing (TD) individuals (N = 189) aged 6 to 30?years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits. RESULTS: We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders. CONCLUSIONS: Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition. En ligne : http://dx.doi.org/10.1186/s13229-020-0317-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Social brain activation during mentalizing in a large autism cohort: the Longitudinal European Autism Project [Texte imprimé et/ou numérique] / Carolin MOESSNANG, Auteur ; Sarah BAUMEISTER, Auteur ; Julian TILLMANN, Auteur ; David GOYARD, Auteur ; Tony CHARMAN, Auteur ; Sara AMBROSINO, Auteur ; Simon BARON-COHEN, Auteur ; Christian F. BECKMANN, Auteur ; Sven BÖLTE, Auteur ; Carsten BOURS, Auteur ; Daisy CRAWLEY, Auteur ; Flavio DELL'ACQUA, Auteur ; Sarah DURSTON, Auteur ; Christine ECKER, Auteur ; Vincent FROUIN, Auteur ; Hannah HAYWARD, Auteur ; Rosemary HOLT, Auteur ; Mark H. JOHNSON, Auteur ; Emily JONES, Auteur ; Meng-Chuan LAI, Auteur ; Michael V. LOMBARDO, Auteur ; Luke MASON, Auteur ; Marianne OLDENHINKEL, Auteur ; Antonio PERSICO, Auteur ; Antonia SAN JOSE CACERES, Auteur ; Will SPOOREN, Auteur ; Eva LOTH, Auteur ; Declan G. M. MURPHY, Auteur ; Jan K. BUITELAAR, Auteur ; Tobias BANASCHEWSKI, Auteur ; Daniel BRANDEIS, Auteur ; Heike TOST, Auteur ; Andreas MEYER-LINDENBERG, Auteur . - 17 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 17 p. Mots-clés : Animated shapes  Autism  Autism spectrum disorder  Development  Mentalizing  Multi-site  Social brain  Theory of mind  fMRI  Science, Atheneum Partners, Blueprint Partnership, Boehringer Ingelheim, Daimler und  Benz Stiftung, Elsevier, F. Hoffmann-La Roche, ICARE Schizophrenia, K. G. Jebsen  Foundation, L.E.K Consulting, Lundbeck International Foundation (LINF), R. Adamczak,  Roche Pharma, Science Foundation, Sumitomo Dainippon Pharma, Synapsis  Foundation–Alzheimer Research Switzerland, and System Analytics, and has received  lectures fees including travel fees from Boehringer Ingelheim, Fama Public  Relations, Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),  Janssen-Cilag, Klinikum Christophsbad, Göppingen, Lilly Deutschland, Luzerner  Psychiatrie, LVR Klinikum Düsseldorf, LWL Psychiatrie Verbund Westfalen-Lippe,  Otsuka Pharmaceuticals, Reunions i Ciencia S. L., Spanish Society of Psychiatry,  Südwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. WM has received  lecture or travel fees from Pfizer, Grünenthal, University of Zürich, International  Association for the Study on Pain (IASP), and European Federation of IASP Chapters  (EFIC). SB discloses that he has in the last 5?years acted as an author, consultant  or lecturer for Shire, Medice, Roche, Eli Lilly, Prima Psychiatry, GLGroup, System  Analytic, Ability Partner, Kompetento, Expo Medica, Clarion Healthcare, and  Prophase. He receives royalties for textbooks and diagnostic tools from  Huber/Hogrefe, Kohlhammer, and UTB. The other authors declare that they have no  competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the "social brain," a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD. METHODS: As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N = 205) and typically developing (TD) individuals (N = 189) aged 6 to 30?years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits. RESULTS: We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders. CONCLUSIONS: Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition. En ligne : http://dx.doi.org/10.1186/s13229-020-0317-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Revised scored Sensory Perception Quotient reveals sensory hypersensitivity in women with autism / Emily TAYLOR in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 18 p. Titre : Revised scored Sensory Perception Quotient reveals sensory hypersensitivity in women with autism Type de document : Texte imprimé et/ou numérique Auteurs : Emily TAYLOR, Auteur ; Rosemary HOLT, Auteur ; Teresa TAVASSOLI, Auteur ; Chris ASHWIN, Auteur ; Simon BARON-COHEN, Auteur Article en page(s) : 18 p. Langues : Anglais (eng) Mots-clés : Autism spectrum conditions  Broader autism phenotype  Hypersensitivity  Sensory  Sensory Perception Quotient  females Index. décimale : PER Périodiques Résumé : BACKGROUND: Previous research using the Sensory Perception Quotient (SPQ) has reported greater sensory hypersensitivity in people with autism spectrum condition (ASC) compared to controls, consistent with other research. However, current scoring of the SPQ does not differentiate between hyper and hyposensitivity, making it uncertain whether individuals with ASC might also show differences in hyposensitivity. Furthermore, no research to date has focused on sensory differences in females, and whether differences in sensory sensitivity extend to the broader autism phenotype (BAP). The present study aimed to fill these gaps. METHODS: The present study developed and validated a Revised Scoring of the Sensory Perception Quotient (SPQ-RS) in order to investigate self-reported hypersensitivity and hyposensitivity in three groups of adults: a female ASC group (n = 152), mothers of children with ASC (BAP mothers group; n = 103), and a control mothers group (n = 74). All participants completed the SPQ as a self-report measure of sensory processing and the Autism-Spectrum Quotient (AQ) as a measure of the degree of autism traits. RESULTS: The female ASC group reported significantly more hypersensitivity, but not more hyposensitivity, compared to the control female and BAP mothers groups. The BAP mothers group did not differ from the control mothers group in either reported hypersensitivity (p = .365) or hyposensitivity (p = .075), suggesting atypical sensory sensitivity is not a BAP trait within females. SPQ-RS hypersensitivity scores positively correlated with autistic traits in the female ASC (r = .266) and BAP mothers groups (r = .350). CONCLUSIONS: The present findings revealed greater sensory hypersensitivity, but not hyposensitivity, in females with ASC compared to BAP and control female groups, and that a greater degree of autism traits relates to higher hypersensitivity in ASC females. The results offer support for the enhanced perceptual functioning model using large samples of females, who are an understudied population, and demonstrate the validity of the SPQ-RS as a valuable new research tool for exploring self-reported hypersensitivity and hyposensitivity. En ligne : http://dx.doi.org/10.1186/s13229-019-0289-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Revised scored Sensory Perception Quotient reveals sensory hypersensitivity in women with autism [Texte imprimé et/ou numérique] / Emily TAYLOR, Auteur ; Rosemary HOLT, Auteur ; Teresa TAVASSOLI, Auteur ; Chris ASHWIN, Auteur ; Simon BARON-COHEN, Auteur . - 18 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 18 p. Mots-clés : Autism spectrum conditions  Broader autism phenotype  Hypersensitivity  Sensory  Sensory Perception Quotient  females Index. décimale : PER Périodiques Résumé : BACKGROUND: Previous research using the Sensory Perception Quotient (SPQ) has reported greater sensory hypersensitivity in people with autism spectrum condition (ASC) compared to controls, consistent with other research. However, current scoring of the SPQ does not differentiate between hyper and hyposensitivity, making it uncertain whether individuals with ASC might also show differences in hyposensitivity. Furthermore, no research to date has focused on sensory differences in females, and whether differences in sensory sensitivity extend to the broader autism phenotype (BAP). The present study aimed to fill these gaps. METHODS: The present study developed and validated a Revised Scoring of the Sensory Perception Quotient (SPQ-RS) in order to investigate self-reported hypersensitivity and hyposensitivity in three groups of adults: a female ASC group (n = 152), mothers of children with ASC (BAP mothers group; n = 103), and a control mothers group (n = 74). All participants completed the SPQ as a self-report measure of sensory processing and the Autism-Spectrum Quotient (AQ) as a measure of the degree of autism traits. RESULTS: The female ASC group reported significantly more hypersensitivity, but not more hyposensitivity, compared to the control female and BAP mothers groups. The BAP mothers group did not differ from the control mothers group in either reported hypersensitivity (p = .365) or hyposensitivity (p = .075), suggesting atypical sensory sensitivity is not a BAP trait within females. SPQ-RS hypersensitivity scores positively correlated with autistic traits in the female ASC (r = .266) and BAP mothers groups (r = .350). CONCLUSIONS: The present findings revealed greater sensory hypersensitivity, but not hyposensitivity, in females with ASC compared to BAP and control female groups, and that a greater degree of autism traits relates to higher hypersensitivity in ASC females. The results offer support for the enhanced perceptual functioning model using large samples of females, who are an understudied population, and demonstrate the validity of the SPQ-RS as a valuable new research tool for exploring self-reported hypersensitivity and hyposensitivity. En ligne : http://dx.doi.org/10.1186/s13229-019-0289-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers / Olga EGOROVA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 7 p. Titre : Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers Type de document : Texte imprimé et/ou numérique Auteurs : Olga EGOROVA, Auteur ; Robin MYTE, Auteur ; Jörn SCHNEEDE, Auteur ; Bruno HAGGLOF, Auteur ; Sven BÖLTE, Auteur ; Erik DOMELLÖF, Auteur ; Barbro IVARS A'ROCH, Auteur ; Fredrik ELGH, Auteur ; Per Magne UELAND, Auteur ; Sven-Arne SILFVERDAL, Auteur Article en page(s) : 7 p. Langues : Anglais (eng) Mots-clés : Autism  Folate  Inflammation  One-carbon metabolism  Pregnancy  Vitamin A  Vitamin B  Vitamin D  that he has in the last 5 years acted as an author, consultant, or lecturer for  Shire, Medice, Roche, Eli Lilly, Prima Psychiatry, GLGroup, System Analytic,  Kompetento, Expo Medica, and Prophase. He receives royalties for text books and  diagnostic tools from Huber/Hogrefe, Kohlhammer and UTB. Erik Domellöf is supported  by a grant from the Knut and Alice Wallenberg Foundation (KAW 2015.0192). There are  no other financial disclosures or conflicts of interest. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis. METHODS: Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B(9)) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation. RESULTS: We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22-2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D(3) levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring. CONCLUSIONS: Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted. En ligne : http://dx.doi.org/10.1186/s13229-020-0315-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers [Texte imprimé et/ou numérique] / Olga EGOROVA, Auteur ; Robin MYTE, Auteur ; Jörn SCHNEEDE, Auteur ; Bruno HAGGLOF, Auteur ; Sven BÖLTE, Auteur ; Erik DOMELLÖF, Auteur ; Barbro IVARS A'ROCH, Auteur ; Fredrik ELGH, Auteur ; Per Magne UELAND, Auteur ; Sven-Arne SILFVERDAL, Auteur . - 7 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 7 p. Mots-clés : Autism  Folate  Inflammation  One-carbon metabolism  Pregnancy  Vitamin A  Vitamin B  Vitamin D  that he has in the last 5 years acted as an author, consultant, or lecturer for  Shire, Medice, Roche, Eli Lilly, Prima Psychiatry, GLGroup, System Analytic,  Kompetento, Expo Medica, and Prophase. He receives royalties for text books and  diagnostic tools from Huber/Hogrefe, Kohlhammer and UTB. Erik Domellöf is supported  by a grant from the Knut and Alice Wallenberg Foundation (KAW 2015.0192). There are  no other financial disclosures or conflicts of interest. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis. METHODS: Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B(9)) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation. RESULTS: We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22-2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D(3) levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring. CONCLUSIONS: Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted. En ligne : http://dx.doi.org/10.1186/s13229-020-0315-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum / Taesun YOO in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 19 p. Titre : A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum Type de document : Texte imprimé et/ou numérique Auteurs : Taesun YOO, Auteur ; Sun-Gyun KIM, Auteur ; Soo Hyun YANG, Auteur ; Hyun KIM, Auteur ; Eunjoon KIM, Auteur ; Soo Young KIM, Auteur Article en page(s) : 19 p. Langues : Anglais (eng) Mots-clés : Autism  Locomotion  psd-93  Self-grooming  Social interaction  Spiny projection Neurons  Striatum Index. décimale : PER Périodiques Résumé : BACKGROUND: DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. METHODS: Mice lacking exon 14 of the Dlg2 gene (Dlg2(-/-) mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. RESULTS: Dlg2(-/-) mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2(-/-) mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2(-/-) dorsolateral striatum was significantly reduced. CONCLUSION: These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2. En ligne : http://dx.doi.org/10.1186/s13229-020-00324-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum [Texte imprimé et/ou numérique] / Taesun YOO, Auteur ; Sun-Gyun KIM, Auteur ; Soo Hyun YANG, Auteur ; Hyun KIM, Auteur ; Eunjoon KIM, Auteur ; Soo Young KIM, Auteur . - 19 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 19 p. Mots-clés : Autism  Locomotion  psd-93  Self-grooming  Social interaction  Spiny projection Neurons  Striatum Index. décimale : PER Périodiques Résumé : BACKGROUND: DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. METHODS: Mice lacking exon 14 of the Dlg2 gene (Dlg2(-/-) mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. RESULTS: Dlg2(-/-) mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2(-/-) mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2(-/-) dorsolateral striatum was significantly reduced. CONCLUSION: These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2. En ligne : http://dx.doi.org/10.1186/s13229-020-00324-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Effects of oxytocin administration on salivary sex hormone levels in autistic and neurotypical women / Tanya L. PROCYSHYN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 20 p. Titre : Effects of oxytocin administration on salivary sex hormone levels in autistic and neurotypical women Type de document : Texte imprimé et/ou numérique Auteurs : Tanya L. PROCYSHYN, Auteur ; Michael V. LOMBARDO, Auteur ; Meng-Chuan LAI, Auteur ; Bonnie AUYEUNG, Auteur ; Sarah K. CROCKFORD, Auteur ; J. DEAKIN, Auteur ; S. SOUBRAMANIAN, Auteur ; A. SULE, Auteur ; Simon BARON-COHEN, Auteur ; Richard A. I. BETHLEHEM, Auteur Article en page(s) : 20 p. Langues : Anglais (eng) Mots-clés : Autism  Autistic women  Oestradiol  Oxytocin  Salivary hormone levels  Sex steroids  Testosterone Index. décimale : PER Périodiques Résumé : BACKGROUND: Oxytocin administration, which may be of therapeutic value for individuals with social difficulties, is likely to affect endogenous levels of other socially relevant hormones. However, to date, the effects of oxytocin administration on endogenous hormones have only been examined in neurotypical individuals. The need to consider multi-hormone interactions is particularly warranted in oxytocin trials for autism due to evidence of irregularities in both oxytocin and sex steroid systems. METHODS: In this double-blind cross-over study, saliva samples were collected from 16 autistic and 29 neurotypical women before and after intranasal administration of 24?IU oxytocin or placebo. Oestradiol, testosterone, and oxytocin levels were quantified in saliva samples. Participants also completed the Autism-Spectrum Quotient (AQ) and Empathy Quotient (EQ) questionnaires. RESULTS: Distinct patterns of change in testosterone and oestradiol levels pre- to-post-administration were observed in autistic relative to neurotypical women (ANCOVA, p < 0.05 main effect of Group), controlling for sample collection time. The mean percent change oestradiol was + 8.8% for the autism group and - 13.0% for the neurotypical group (t = 1.81, p = 0.08), while the mean percent change testosterone was + 1.1% in the autism group and - 12.6% in the neurotypical group (t = 1.26, p = 0.22). In the oxytocin condition, the mean percent change oestradiol was + 12.6% in the autism group and - 6.9% in the neurotypical group (t = 1.78, p = 0.08), while the mean percent change testosterone was + 14.4% in the autism group and - 15.2% in the neurotypical group (t = 3.00, p = 0.006). Robust regression confirmed that group differences in percent change hormone levels were not driven by a small number of influential individuals. Baseline hormone levels did not differ between groups when considered individually. However, baseline testosterone relative to oestradiol (T:E2 ratio) was higher in autistic women (p = 0.023, Cohen's d = 0.63), and this ratio correlated positively and negatively with AQ and EQ scores, respectively, in the combined sample. LIMITATIONS: Further studies with larger and more diverse autistic sample are warranted to confirm these effects. CONCLUSIONS: This study provides the first evidence that oxytocin influences endogenous testosterone levels in autistic individuals, with autistic women showing increases similar to previous reports of neurotypical men. These findings highlight the need to consider sex steroid hormones as a variable in future oxytocin trials. En ligne : http://dx.doi.org/10.1186/s13229-020-00326-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Effects of oxytocin administration on salivary sex hormone levels in autistic and neurotypical women [Texte imprimé et/ou numérique] / Tanya L. PROCYSHYN, Auteur ; Michael V. LOMBARDO, Auteur ; Meng-Chuan LAI, Auteur ; Bonnie AUYEUNG, Auteur ; Sarah K. CROCKFORD, Auteur ; J. DEAKIN, Auteur ; S. SOUBRAMANIAN, Auteur ; A. SULE, Auteur ; Simon BARON-COHEN, Auteur ; Richard A. I. BETHLEHEM, Auteur . - 20 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 20 p. Mots-clés : Autism  Autistic women  Oestradiol  Oxytocin  Salivary hormone levels  Sex steroids  Testosterone Index. décimale : PER Périodiques Résumé : BACKGROUND: Oxytocin administration, which may be of therapeutic value for individuals with social difficulties, is likely to affect endogenous levels of other socially relevant hormones. However, to date, the effects of oxytocin administration on endogenous hormones have only been examined in neurotypical individuals. The need to consider multi-hormone interactions is particularly warranted in oxytocin trials for autism due to evidence of irregularities in both oxytocin and sex steroid systems. METHODS: In this double-blind cross-over study, saliva samples were collected from 16 autistic and 29 neurotypical women before and after intranasal administration of 24?IU oxytocin or placebo. Oestradiol, testosterone, and oxytocin levels were quantified in saliva samples. Participants also completed the Autism-Spectrum Quotient (AQ) and Empathy Quotient (EQ) questionnaires. RESULTS: Distinct patterns of change in testosterone and oestradiol levels pre- to-post-administration were observed in autistic relative to neurotypical women (ANCOVA, p < 0.05 main effect of Group), controlling for sample collection time. The mean percent change oestradiol was + 8.8% for the autism group and - 13.0% for the neurotypical group (t = 1.81, p = 0.08), while the mean percent change testosterone was + 1.1% in the autism group and - 12.6% in the neurotypical group (t = 1.26, p = 0.22). In the oxytocin condition, the mean percent change oestradiol was + 12.6% in the autism group and - 6.9% in the neurotypical group (t = 1.78, p = 0.08), while the mean percent change testosterone was + 14.4% in the autism group and - 15.2% in the neurotypical group (t = 3.00, p = 0.006). Robust regression confirmed that group differences in percent change hormone levels were not driven by a small number of influential individuals. Baseline hormone levels did not differ between groups when considered individually. However, baseline testosterone relative to oestradiol (T:E2 ratio) was higher in autistic women (p = 0.023, Cohen's d = 0.63), and this ratio correlated positively and negatively with AQ and EQ scores, respectively, in the combined sample. LIMITATIONS: Further studies with larger and more diverse autistic sample are warranted to confirm these effects. CONCLUSIONS: This study provides the first evidence that oxytocin influences endogenous testosterone levels in autistic individuals, with autistic women showing increases similar to previous reports of neurotypical men. These findings highlight the need to consider sex steroid hormones as a variable in future oxytocin trials. En ligne : http://dx.doi.org/10.1186/s13229-020-00326-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits / Julien FREGEAC in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 22 p. Titre : Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits Type de document : Texte imprimé et/ou numérique Auteurs : Julien FREGEAC, Auteur ; Stéphanie MORICEAU, Auteur ; Antoine POLI, Auteur ; Lam Son NGUYEN, Auteur ; Franck OURY, Auteur ; Laurence COLLEAUX, Auteur Article en page(s) : 22 p. Langues : Anglais (eng) Mots-clés : Hippocampus-dependent cognitive functions  MicroRNA  Neural stem cells differentiation  Neurodevelopment  Neurodevelopmental disorders  miR-146a Index. décimale : PER Périodiques Résumé : BACKGROUND: Formation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear. METHODS: Using a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD). RESULTS: We first show that during development, loss of miR-146a impairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss of miR-146a correlates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation of miR-146a in adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions. CONCLUSION: Our results show that miR-146a expression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role of miR-146a in regulating hippocampal-dependent memory. Furthermore, the demonstration that the Mir146a(-/-) mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation of miR146a contributes to the pathogenesis of DBDs. En ligne : http://dx.doi.org/10.1186/s13229-020-00328-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Loss of the neurodevelopmental disease-associated gene miR-146a impairs neural progenitor differentiation and causes learning and memory deficits [Texte imprimé et/ou numérique] / Julien FREGEAC, Auteur ; Stéphanie MORICEAU, Auteur ; Antoine POLI, Auteur ; Lam Son NGUYEN, Auteur ; Franck OURY, Auteur ; Laurence COLLEAUX, Auteur . - 22 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 22 p. Mots-clés : Hippocampus-dependent cognitive functions  MicroRNA  Neural stem cells differentiation  Neurodevelopment  Neurodevelopmental disorders  miR-146a Index. décimale : PER Périodiques Résumé : BACKGROUND: Formation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear. METHODS: Using a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD). RESULTS: We first show that during development, loss of miR-146a impairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss of miR-146a correlates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation of miR-146a in adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions. CONCLUSION: Our results show that miR-146a expression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role of miR-146a in regulating hippocampal-dependent memory. Furthermore, the demonstration that the Mir146a(-/-) mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation of miR146a contributes to the pathogenesis of DBDs. En ligne : http://dx.doi.org/10.1186/s13229-020-00328-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? / Karina A. KRUTH in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 23 p. Titre : SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? Type de document : Texte imprimé et/ou numérique Auteurs : Karina A. KRUTH, Auteur ; Tierney M. GRISOLANO, Auteur ; Christopher A. AHERN, Auteur ; Aislinn J. WILLIAMS, Auteur Article en page(s) : 23 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Cell model  Induced pluripotent stem cell  NaV1.2  Organoid  scn2a  SCN2A syndrome  Sodium channel Index. décimale : PER Périodiques Résumé : Efforts to identify the causes of autism spectrum disorders have highlighted the importance of both genetics and environment, but the lack of human models for many of these disorders limits researchers' attempts to understand the mechanisms of disease and to develop new treatments. Induced pluripotent stem cells offer the opportunity to study specific genetic and environmental risk factors, but the heterogeneity of donor genetics may obscure important findings. Diseases associated with unusually high rates of autism, such as SCN2A syndromes, provide an opportunity to study specific mutations with high effect sizes in a human genetic context and may reveal biological insights applicable to more common forms of autism. Loss-of-function mutations in the SCN2A gene, which encodes the voltage-gated sodium channel Na(V)1.2, are associated with autism rates up to 50%. Here, we review the findings from experimental models of SCN2A syndromes, including mouse and human cell studies, highlighting the potential role for patient-derived induced pluripotent stem cell technology to identify the molecular and cellular substrates of autism. En ligne : http://dx.doi.org/10.1186/s13229-020-00330-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? [Texte imprimé et/ou numérique] / Karina A. KRUTH, Auteur ; Tierney M. GRISOLANO, Auteur ; Christopher A. AHERN, Auteur ; Aislinn J. WILLIAMS, Auteur . - 23 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 23 p. Mots-clés : Autism spectrum disorder  Cell model  Induced pluripotent stem cell  NaV1.2  Organoid  scn2a  SCN2A syndrome  Sodium channel Index. décimale : PER Périodiques Résumé : Efforts to identify the causes of autism spectrum disorders have highlighted the importance of both genetics and environment, but the lack of human models for many of these disorders limits researchers' attempts to understand the mechanisms of disease and to develop new treatments. Induced pluripotent stem cells offer the opportunity to study specific genetic and environmental risk factors, but the heterogeneity of donor genetics may obscure important findings. Diseases associated with unusually high rates of autism, such as SCN2A syndromes, provide an opportunity to study specific mutations with high effect sizes in a human genetic context and may reveal biological insights applicable to more common forms of autism. Loss-of-function mutations in the SCN2A gene, which encodes the voltage-gated sodium channel Na(V)1.2, are associated with autism rates up to 50%. Here, we review the findings from experimental models of SCN2A syndromes, including mouse and human cell studies, highlighting the potential role for patient-derived induced pluripotent stem cell technology to identify the molecular and cellular substrates of autism. En ligne : http://dx.doi.org/10.1186/s13229-020-00330-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Developmental changes in attention to social information from childhood to adolescence in autism spectrum disorders: a comparative study / Toru FUJIOKA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 24 p. Titre : Developmental changes in attention to social information from childhood to adolescence in autism spectrum disorders: a comparative study Type de document : Texte imprimé et/ou numérique Auteurs : Toru FUJIOKA, Auteur ; Kenji J. TSUCHIYA, Auteur ; Manabu SAITO, Auteur ; Yoshiyuki HIRANO, Auteur ; Muneaki MATSUO, Auteur ; Mitsuru KIKUCHI, Auteur ; Yoshihiro MAEGAKI, Auteur ; Damee CHOI, Auteur ; Sumi KATO, Auteur ; Tokiko YOSHIDA, Auteur ; Yuko YOSHIMURA, Auteur ; Sawako OOBA, Auteur ; Yoshifumi MIZUNO, Auteur ; Shinichiro TAKIGUCHI, Auteur ; Hideo MATSUZAKI, Auteur ; Akemi TOMODA, Auteur ; Katsuyuki SHUDO, Auteur ; Masaru NINOMIYA, Auteur ; Taiichi KATAYAMA, Auteur ; Hirotaka KOSAKA, Auteur Article en page(s) : 24 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Developmental change  Eye-tracking  Social information Index. décimale : PER Périodiques Résumé : BACKGROUND: Elucidating developmental changes in the symptoms of autism spectrum disorder (ASD) is important to support individuals with ASD. However, no report has clarified the developmental changes in attention to social information for a broad age range. The aim of this study was to investigate the developmental changes in attention to social information from early childhood to adolescence in individuals with ASD and typically developed (TD) children. METHODS: We recruited children with ASD (n = 83) and TD participants (n = 307) between 2 and 18?years of age. Using the all-in-one-eye-tracking system, Gazefinder, we measured the percentage fixation time allocated to areas of interest (AoIs) depicted in movies (the eyes and mouth in movies of a human face with/without mouth motion, upright and inverted biological motion in movies showing these stimuli simultaneously, people and geometry in preference paradigm movies showing these stimuli simultaneously, and objects with/without finger-pointing in a movie showing a woman pointing toward an object). We conducted a three-way analysis of variance, 2 (diagnosis: ASD and TD) by 2 (sex: male and female) by 3 (age group: 0-5, 6-11, and 12-18 years) and locally weighted the scatterplot smoothing (LOESS) regression curve on each AoI. RESULTS: In the face stimuli, the percentage fixation time to the eye region for the TD group increased with age, whereas the one for the ASD group did not. In the ASD group, the LOESS curves of the gaze ratios at the eye region increased up to approximately 10?years of age and thereafter tended to decrease. For the percentage fixation time to the people region in the preference paradigm, the ASD group gazed more briefly at people than did the TD group. LIMITATIONS: It is possible that due to the cross-sectional design, the degree of severity and of social interest might have differed according to the subjects' age. CONCLUSIONS: There may be qualitative differences in abnormal eye contact in ASD between individuals in early childhood and those older than 10?years. En ligne : http://dx.doi.org/10.1186/s13229-020-00321-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Developmental changes in attention to social information from childhood to adolescence in autism spectrum disorders: a comparative study [Texte imprimé et/ou numérique] / Toru FUJIOKA, Auteur ; Kenji J. TSUCHIYA, Auteur ; Manabu SAITO, Auteur ; Yoshiyuki HIRANO, Auteur ; Muneaki MATSUO, Auteur ; Mitsuru KIKUCHI, Auteur ; Yoshihiro MAEGAKI, Auteur ; Damee CHOI, Auteur ; Sumi KATO, Auteur ; Tokiko YOSHIDA, Auteur ; Yuko YOSHIMURA, Auteur ; Sawako OOBA, Auteur ; Yoshifumi MIZUNO, Auteur ; Shinichiro TAKIGUCHI, Auteur ; Hideo MATSUZAKI, Auteur ; Akemi TOMODA, Auteur ; Katsuyuki SHUDO, Auteur ; Masaru NINOMIYA, Auteur ; Taiichi KATAYAMA, Auteur ; Hirotaka KOSAKA, Auteur . - 24 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 24 p. Mots-clés : Autism spectrum disorder  Developmental change  Eye-tracking  Social information Index. décimale : PER Périodiques Résumé : BACKGROUND: Elucidating developmental changes in the symptoms of autism spectrum disorder (ASD) is important to support individuals with ASD. However, no report has clarified the developmental changes in attention to social information for a broad age range. The aim of this study was to investigate the developmental changes in attention to social information from early childhood to adolescence in individuals with ASD and typically developed (TD) children. METHODS: We recruited children with ASD (n = 83) and TD participants (n = 307) between 2 and 18?years of age. Using the all-in-one-eye-tracking system, Gazefinder, we measured the percentage fixation time allocated to areas of interest (AoIs) depicted in movies (the eyes and mouth in movies of a human face with/without mouth motion, upright and inverted biological motion in movies showing these stimuli simultaneously, people and geometry in preference paradigm movies showing these stimuli simultaneously, and objects with/without finger-pointing in a movie showing a woman pointing toward an object). We conducted a three-way analysis of variance, 2 (diagnosis: ASD and TD) by 2 (sex: male and female) by 3 (age group: 0-5, 6-11, and 12-18 years) and locally weighted the scatterplot smoothing (LOESS) regression curve on each AoI. RESULTS: In the face stimuli, the percentage fixation time to the eye region for the TD group increased with age, whereas the one for the ASD group did not. In the ASD group, the LOESS curves of the gaze ratios at the eye region increased up to approximately 10?years of age and thereafter tended to decrease. For the percentage fixation time to the people region in the preference paradigm, the ASD group gazed more briefly at people than did the TD group. LIMITATIONS: It is possible that due to the cross-sectional design, the degree of severity and of social interest might have differed according to the subjects' age. CONCLUSIONS: There may be qualitative differences in abnormal eye contact in ASD between individuals in early childhood and those older than 10?years. En ligne : http://dx.doi.org/10.1186/s13229-020-00321-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

The relationship of autistic traits to taste and olfactory processing in anorexia nervosa / Emma KINNAIRD in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 25 p. Titre : The relationship of autistic traits to taste and olfactory processing in anorexia nervosa Type de document : Texte imprimé et/ou numérique Auteurs : Emma KINNAIRD, Auteur ; Catherine STEWART, Auteur ; Kate TCHANTURIA, Auteur Article en page(s) : 25 p. Langues : Anglais (eng) Mots-clés : Anorexia nervosa  Autism  Eating disorders  Olfaction  Sensory  Taste Index. décimale : PER Périodiques Résumé : BACKGROUND: There is a heightened prevalence of autism in anorexia nervosa (AN) compared to the general population. Autistic people with AN experience a longer illness duration and poorer treatment outcomes. Whether sensory differences in autism could contribute to altered taste and smell as a potential maintaining factor in AN is under-explored. The aim of this study was to explore whether autistic traits are associated with taste and olfaction differences in AN. METHODS: The study recruited n = 40 people with AN, and n = 40 healthy controls (HC). Smell sensitivity was measured using the Sniffin' Sticks test. Taste sensitivity was measured using taste strips. Participants self-rated their autistic traits using the Autism Spectrum Quotient. RESULTS: There were no significant differences on taste and olfactory outcomes between people with AN and HC. These findings did not change after controlling for the heightened levels of autistic traits in the AN group. No relationship between taste and smell outcomes and autistic traits were identified within the AN group. LIMITATIONS: The current study is not able to draw conclusions about taste and smell processing in co-occurring autism and AN as it only measured levels of autistic traits, rather than comparing people with and without an autism diagnosis. CONCLUSIONS: No significant associations between autistic traits and taste and smell processing in AN were identified. Future research should consider further exploring this area, including by comparing autistic women to women with AN. En ligne : http://dx.doi.org/10.1186/s13229-020-00331-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] The relationship of autistic traits to taste and olfactory processing in anorexia nervosa [Texte imprimé et/ou numérique] / Emma KINNAIRD, Auteur ; Catherine STEWART, Auteur ; Kate TCHANTURIA, Auteur . - 25 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 25 p. Mots-clés : Anorexia nervosa  Autism  Eating disorders  Olfaction  Sensory  Taste Index. décimale : PER Périodiques Résumé : BACKGROUND: There is a heightened prevalence of autism in anorexia nervosa (AN) compared to the general population. Autistic people with AN experience a longer illness duration and poorer treatment outcomes. Whether sensory differences in autism could contribute to altered taste and smell as a potential maintaining factor in AN is under-explored. The aim of this study was to explore whether autistic traits are associated with taste and olfaction differences in AN. METHODS: The study recruited n = 40 people with AN, and n = 40 healthy controls (HC). Smell sensitivity was measured using the Sniffin' Sticks test. Taste sensitivity was measured using taste strips. Participants self-rated their autistic traits using the Autism Spectrum Quotient. RESULTS: There were no significant differences on taste and olfactory outcomes between people with AN and HC. These findings did not change after controlling for the heightened levels of autistic traits in the AN group. No relationship between taste and smell outcomes and autistic traits were identified within the AN group. LIMITATIONS: The current study is not able to draw conclusions about taste and smell processing in co-occurring autism and AN as it only measured levels of autistic traits, rather than comparing people with and without an autism diagnosis. CONCLUSIONS: No significant associations between autistic traits and taste and smell processing in AN were identified. Future research should consider further exploring this area, including by comparing autistic women to women with AN. En ligne : http://dx.doi.org/10.1186/s13229-020-00331-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Using human pluripotent stem cell models to study autism in the era of big data / Ralda NEHME in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 21 p. Titre : Using human pluripotent stem cell models to study autism in the era of big data Type de document : Texte imprimé et/ou numérique Auteurs : Ralda NEHME, Auteur ; Lindy E. BARRETT, Auteur Article en page(s) : 21 p. Langues : Anglais (eng) Mots-clés : Differentiation  esc  Human brain  In vivo  Regulatory policy  Sample size  Variance  hPSC  iPSC Index. décimale : PER Périodiques Résumé : Advances in human pluripotent stem cell (hPSC) biology coupled with protocols to generate diverse brain cell types in vitro have provided neuroscientists with opportunities to dissect basic and disease mechanisms in increasingly relevant cellular substrates. At the same time, large data collections and analyses have facilitated unprecedented insights into autism genetics, normal human genetic variation, and the molecular landscape of the developing human brain. While such insights have enabled the investigation of key mechanistic questions in autism, they also highlight important limitations associated with the use of existing hPSC models. In this review, we discuss four such issues which influence the efficacy of hPSC models for studying autism, including (i) sources of variance, (ii) scale and format of study design, (iii) divergence from the human brain in vivo, and (iv) regulatory policies and compliance governing the use of hPSCs. Moreover, we advocate for a set of immediate and long-term priorities to address these issues and to accelerate the generation and reproducibility of data in order to facilitate future fundamental as well as therapeutic discoveries. En ligne : http://dx.doi.org/10.1186/s13229-020-00322-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Using human pluripotent stem cell models to study autism in the era of big data [Texte imprimé et/ou numérique] / Ralda NEHME, Auteur ; Lindy E. BARRETT, Auteur . - 21 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 21 p. Mots-clés : Differentiation  esc  Human brain  In vivo  Regulatory policy  Sample size  Variance  hPSC  iPSC Index. décimale : PER Périodiques Résumé : Advances in human pluripotent stem cell (hPSC) biology coupled with protocols to generate diverse brain cell types in vitro have provided neuroscientists with opportunities to dissect basic and disease mechanisms in increasingly relevant cellular substrates. At the same time, large data collections and analyses have facilitated unprecedented insights into autism genetics, normal human genetic variation, and the molecular landscape of the developing human brain. While such insights have enabled the investigation of key mechanistic questions in autism, they also highlight important limitations associated with the use of existing hPSC models. In this review, we discuss four such issues which influence the efficacy of hPSC models for studying autism, including (i) sources of variance, (ii) scale and format of study design, (iii) divergence from the human brain in vivo, and (iv) regulatory policies and compliance governing the use of hPSCs. Moreover, we advocate for a set of immediate and long-term priorities to address these issues and to accelerate the generation and reproducibility of data in order to facilitate future fundamental as well as therapeutic discoveries. En ligne : http://dx.doi.org/10.1186/s13229-020-00322-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Human in vitro models for understanding mechanisms of autism spectrum disorder / Aaron GORDON in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 26 p. Titre : Human in vitro models for understanding mechanisms of autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Aaron GORDON, Auteur ; Daniel H. GESCHWIND, Auteur Article en page(s) : 26 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled. En ligne : http://dx.doi.org/10.1186/s13229-020-00332-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Human in vitro models for understanding mechanisms of autism spectrum disorder [Texte imprimé et/ou numérique] / Aaron GORDON, Auteur ; Daniel H. GESCHWIND, Auteur . - 26 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 26 p. Index. décimale : PER Périodiques Résumé : Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled. En ligne : http://dx.doi.org/10.1186/s13229-020-00332-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Emerging proteomic approaches to identify the underlying pathophysiology of neurodevelopmental and neurodegenerative disorders / Nadeem MURTAZA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 27 p. Titre : Emerging proteomic approaches to identify the underlying pathophysiology of neurodevelopmental and neurodegenerative disorders Type de document : Texte imprimé et/ou numérique Auteurs : Nadeem MURTAZA, Auteur ; Jarryll UY, Auteur ; Karun K. SINGH, Auteur Article en page(s) : 27 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Proteomics is the large-scale study of the total protein content and their overall function within a cell through multiple facets of research. Advancements in proteomic methods have moved past the simple quantification of proteins to the identification of post-translational modifications (PTMs) and the ability to probe interactions between these proteins, spatially and temporally. Increased sensitivity and resolution of mass spectrometers and sample preparation protocols have drastically reduced the large amount of cells required and the experimental variability that had previously hindered its use in studying human neurological disorders. Proteomics offers a new perspective to study the altered molecular pathways and networks that are associated with autism spectrum disorders (ASD). The differences between the transcriptome and proteome, combined with the various types of post-translation modifications that regulate protein function and localization, highlight a novel level of research that has not been appropriately investigated. In this review, we will discuss strategies using proteomics to study ASD and other neurological disorders, with a focus on how these approaches can be combined with induced pluripotent stem cell (iPSC) studies. Proteomic analysis of iPSC-derived neurons have already been used to measure changes in the proteome caused by patient mutations, analyze changes in PTMs that resulted in altered biological pathways, and identify potential biomarkers. Further advancements in both proteomic techniques and human iPSC differentiation protocols will continue to push the field towards better understanding ASD disease pathophysiology. Proteomics using iPSC-derived neurons from individuals with ASD offers a window for observing the altered proteome, which is necessary in the future development of therapeutics against specific targets. En ligne : http://dx.doi.org/10.1186/s13229-020-00334-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Emerging proteomic approaches to identify the underlying pathophysiology of neurodevelopmental and neurodegenerative disorders [Texte imprimé et/ou numérique] / Nadeem MURTAZA, Auteur ; Jarryll UY, Auteur ; Karun K. SINGH, Auteur . - 27 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 27 p. Index. décimale : PER Périodiques Résumé : Proteomics is the large-scale study of the total protein content and their overall function within a cell through multiple facets of research. Advancements in proteomic methods have moved past the simple quantification of proteins to the identification of post-translational modifications (PTMs) and the ability to probe interactions between these proteins, spatially and temporally. Increased sensitivity and resolution of mass spectrometers and sample preparation protocols have drastically reduced the large amount of cells required and the experimental variability that had previously hindered its use in studying human neurological disorders. Proteomics offers a new perspective to study the altered molecular pathways and networks that are associated with autism spectrum disorders (ASD). The differences between the transcriptome and proteome, combined with the various types of post-translation modifications that regulate protein function and localization, highlight a novel level of research that has not been appropriately investigated. In this review, we will discuss strategies using proteomics to study ASD and other neurological disorders, with a focus on how these approaches can be combined with induced pluripotent stem cell (iPSC) studies. Proteomic analysis of iPSC-derived neurons have already been used to measure changes in the proteome caused by patient mutations, analyze changes in PTMs that resulted in altered biological pathways, and identify potential biomarkers. Further advancements in both proteomic techniques and human iPSC differentiation protocols will continue to push the field towards better understanding ASD disease pathophysiology. Proteomics using iPSC-derived neurons from individuals with ASD offers a window for observing the altered proteome, which is necessary in the future development of therapeutics against specific targets. En ligne : http://dx.doi.org/10.1186/s13229-020-00334-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Inattention and hyperactive/impulsive component scores do not differentiate between autism spectrum disorder and attention-deficit/hyperactivity disorder in a clinical sample / Aneta D. KRAKOWSKI in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 28 p. Titre : Inattention and hyperactive/impulsive component scores do not differentiate between autism spectrum disorder and attention-deficit/hyperactivity disorder in a clinical sample Type de document : Texte imprimé et/ou numérique Auteurs : Aneta D. KRAKOWSKI, Auteur ; Katherine Tombeau COST, Auteur ; Evdokia ANAGNOSTOU, Auteur ; Meng-Chuan LAI, Auteur ; Jennifer CROSBIE, Auteur ; Russell SCHACHAR, Auteur ; Stelios GEORGIADES, Auteur ; Eric DUKU, Auteur ; Peter SZATMARI, Auteur Année de publication : 2020 Article en page(s) : 28 p. Langues : Anglais (eng) Mots-clés : adhd  asd  Co-morbidity  Gender  Principle component analysis  Symptoms  scientific advisory board for ehave (psychological software company). RS also has  equity in ehave. EA has received consultation fees from Roche and Takeda, royalties  from APPI and Springer, and funding from SynapDx and Sanofi-Aventis. PS has received  royalties from Guilford Press. AK, KTC, MCL, JC, ED, and SG have no conflicts of  interest to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: Although there is high co-occurrence between ASD and ADHD, the nature of this co-occurrence remains unclear. Our study aimed to examine the underlying relationship between ASD and ADHD symptoms in a combined sample of children with a primary clinical diagnosis of ASD or ADHD. METHODS: Participants included children and youth (aged 3-20?years) with a clinical diagnosis of ASD (n = 303) or ADHD (n = 319) for a total of 622 participants. Parents of these children completed the social communication questionnaire (SCQ), a measure of autism symptoms, and the strengths and weaknesses of ADHD and normal behavior (SWAN) questionnaire, a measure of ADHD symptoms. A principal component analysis (PCA) was performed on combined SCQ and SWAN items, followed by a profile analysis comparing normalized component scores between diagnostic groups and gender. RESULTS: PCA revealed a four-component solution (inattention, hyperactivity/impulsivity, social-communication, and restricted, repetitive, behaviors, and interests (RRBI)), with no overlap between SCQ and SWAN items in the components. Children with ASD had higher component scores in social-communication and RRBI than children with ADHD, while there was no difference in inattentive and hyperactive/impulsive scores between diagnostic groups. Males had higher scores than females in social-communication, RRBI, and hyperactivity/impulsivity components in each diagnostic group. LIMITATIONS: We did not formally assess children with ASD for ADHD using our research-criteria for ADHD, and vice versa. High rates of co-occurring ADHD in ASD, for example, may have inflated component scores in inattention and hyperactivity/impulsivity. A disadvantage with using single informant-based reports (i.e., parent-rated questionnaires) is that ASD and ADHD symptoms may be difficult to distinguish by parents, and may be interpreted differently between parents and clinicians. CONCLUSIONS: ASD and ADHD items loaded on separate components in our sample, suggesting that the measurement structure cannot explain the covariation between the two disorders in clinical samples. High levels of inattention and hyperactivity/impulsivity were seen in both ASD and ADHD in our clinical sample. This supports the need for a dimensional framework that examines neurodevelopmental domains across traditional diagnostic boundaries. Females also had lower component scores across social-communication, RRBI, and hyperactivity/impulsivity than males, suggesting that there may be gender-specific phenotypes related to the two conditions. En ligne : http://dx.doi.org/10.1186/s13229-020-00338-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Inattention and hyperactive/impulsive component scores do not differentiate between autism spectrum disorder and attention-deficit/hyperactivity disorder in a clinical sample [Texte imprimé et/ou numérique] / Aneta D. KRAKOWSKI, Auteur ; Katherine Tombeau COST, Auteur ; Evdokia ANAGNOSTOU, Auteur ; Meng-Chuan LAI, Auteur ; Jennifer CROSBIE, Auteur ; Russell SCHACHAR, Auteur ; Stelios GEORGIADES, Auteur ; Eric DUKU, Auteur ; Peter SZATMARI, Auteur . - 2020 . - 28 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 28 p. Mots-clés : adhd  asd  Co-morbidity  Gender  Principle component analysis  Symptoms  scientific advisory board for ehave (psychological software company). RS also has  equity in ehave. EA has received consultation fees from Roche and Takeda, royalties  from APPI and Springer, and funding from SynapDx and Sanofi-Aventis. PS has received  royalties from Guilford Press. AK, KTC, MCL, JC, ED, and SG have no conflicts of  interest to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: Although there is high co-occurrence between ASD and ADHD, the nature of this co-occurrence remains unclear. Our study aimed to examine the underlying relationship between ASD and ADHD symptoms in a combined sample of children with a primary clinical diagnosis of ASD or ADHD. METHODS: Participants included children and youth (aged 3-20?years) with a clinical diagnosis of ASD (n = 303) or ADHD (n = 319) for a total of 622 participants. Parents of these children completed the social communication questionnaire (SCQ), a measure of autism symptoms, and the strengths and weaknesses of ADHD and normal behavior (SWAN) questionnaire, a measure of ADHD symptoms. A principal component analysis (PCA) was performed on combined SCQ and SWAN items, followed by a profile analysis comparing normalized component scores between diagnostic groups and gender. RESULTS: PCA revealed a four-component solution (inattention, hyperactivity/impulsivity, social-communication, and restricted, repetitive, behaviors, and interests (RRBI)), with no overlap between SCQ and SWAN items in the components. Children with ASD had higher component scores in social-communication and RRBI than children with ADHD, while there was no difference in inattentive and hyperactive/impulsive scores between diagnostic groups. Males had higher scores than females in social-communication, RRBI, and hyperactivity/impulsivity components in each diagnostic group. LIMITATIONS: We did not formally assess children with ASD for ADHD using our research-criteria for ADHD, and vice versa. High rates of co-occurring ADHD in ASD, for example, may have inflated component scores in inattention and hyperactivity/impulsivity. A disadvantage with using single informant-based reports (i.e., parent-rated questionnaires) is that ASD and ADHD symptoms may be difficult to distinguish by parents, and may be interpreted differently between parents and clinicians. CONCLUSIONS: ASD and ADHD items loaded on separate components in our sample, suggesting that the measurement structure cannot explain the covariation between the two disorders in clinical samples. High levels of inattention and hyperactivity/impulsivity were seen in both ASD and ADHD in our clinical sample. This supports the need for a dimensional framework that examines neurodevelopmental domains across traditional diagnostic boundaries. Females also had lower component scores across social-communication, RRBI, and hyperactivity/impulsivity than males, suggesting that there may be gender-specific phenotypes related to the two conditions. En ligne : http://dx.doi.org/10.1186/s13229-020-00338-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Tsc1 haploinsufficiency in Nkx2.1 cells upregulates hippocampal interneuron mTORC1 activity, impairs pyramidal cell synaptic inhibition, and alters contextual fear discrimination and spatial working memory in mice / Nabila HAJI in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 29 p. Titre : Tsc1 haploinsufficiency in Nkx2.1 cells upregulates hippocampal interneuron mTORC1 activity, impairs pyramidal cell synaptic inhibition, and alters contextual fear discrimination and spatial working memory in mice Type de document : Texte imprimé et/ou numérique Auteurs : Nabila HAJI, Auteur ; Ilse RIEBE, Auteur ; Argel AGUILAR-VALLES, Auteur ; Julien ARTINIAN, Auteur ; Isabel LAPLANTE, Auteur ; Jean-Claude LACAILLE, Auteur Article en page(s) : 29 p. Langues : Anglais (eng) Mots-clés : Autism mouse model  Contextual fear conditioning  Inhibitory interneurons  Spatial learning  Tuberous sclerosis  Whole-cell recordings  mTORC1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC), a disorder associated with epilepsy, autism, and intellectual disability. TSC1 and TSC2 are repressors of the mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of protein synthesis. Dysregulation of mTORC1 in TSC mouse models leads to impairments in excitation-inhibition balance, synaptic plasticity, and hippocampus-dependent learning and memory deficits. However, synaptic inhibition arises from multiple types of inhibitory interneurons and how changes in specific interneurons contribute to TSC remains largely unknown. In the present work, we determined the effect of conditional Tsc1 haploinsufficiency in a specific subgroup of inhibitory cells on hippocampal function in mice. METHODS: We investigated the consequences of conditional heterozygous knockout of Tsc1 in MGE-derived inhibitory cells by crossing Nkx2.1(Cre/wt);Tsc1(f/f) mice. We examined the changes in mTORC1 activity and synaptic transmission in hippocampal cells, as well as hippocampus-related cognitive tasks. RESULTS: We detected selective increases in phosphorylation of ribosomal protein S6 in interneurons, indicating cell-specific-upregulated mTORC1 signaling. At the behavioral level, Nkx2.1(Cre/wt);Tsc1(f/wt) mice exhibited intact contextual fear memory, but impaired contextual fear discrimination. They displayed intact spatial learning and reference memory but impairment in spatial working memory. Whole-cell recordings in hippocampal slices of Nkx2.1(Cre/wt);Tsc1(f/wt) mice showed intact basic membrane properties, as well as miniature excitatory and inhibitory synaptic transmission, in pyramidal and Nkx2.1-expressing inhibitory cells. Using optogenetic activation of Nkx2.1 interneurons in slices of Nkx2.1(Cre/wt);Tsc1(f/wt) mice, we found a decrease in synaptic inhibition of pyramidal cells. Chronic, but not acute treatment, with the mTORC1 inhibitor rapamycin reversed the impairment in synaptic inhibition. CONCLUSIONS: Our results indicate that Tsc1 haploinsufficiency in MGE-derived inhibitory cells upregulates mTORC1 activity in these interneurons, reduces their synaptic inhibition of pyramidal cells, and alters contextual fear discrimination and spatial working memory. Thus, selective dysregulation of mTORC1 function in Nkx2.1-expressing inhibitory cells appears sufficient to impair synaptic inhibition and contributes to cognitive deficits in the Tsc1 mouse model of TSC. En ligne : http://dx.doi.org/10.1186/s13229-020-00340-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Tsc1 haploinsufficiency in Nkx2.1 cells upregulates hippocampal interneuron mTORC1 activity, impairs pyramidal cell synaptic inhibition, and alters contextual fear discrimination and spatial working memory in mice [Texte imprimé et/ou numérique] / Nabila HAJI, Auteur ; Ilse RIEBE, Auteur ; Argel AGUILAR-VALLES, Auteur ; Julien ARTINIAN, Auteur ; Isabel LAPLANTE, Auteur ; Jean-Claude LACAILLE, Auteur . - 29 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 29 p. Mots-clés : Autism mouse model  Contextual fear conditioning  Inhibitory interneurons  Spatial learning  Tuberous sclerosis  Whole-cell recordings  mTORC1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC), a disorder associated with epilepsy, autism, and intellectual disability. TSC1 and TSC2 are repressors of the mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of protein synthesis. Dysregulation of mTORC1 in TSC mouse models leads to impairments in excitation-inhibition balance, synaptic plasticity, and hippocampus-dependent learning and memory deficits. However, synaptic inhibition arises from multiple types of inhibitory interneurons and how changes in specific interneurons contribute to TSC remains largely unknown. In the present work, we determined the effect of conditional Tsc1 haploinsufficiency in a specific subgroup of inhibitory cells on hippocampal function in mice. METHODS: We investigated the consequences of conditional heterozygous knockout of Tsc1 in MGE-derived inhibitory cells by crossing Nkx2.1(Cre/wt);Tsc1(f/f) mice. We examined the changes in mTORC1 activity and synaptic transmission in hippocampal cells, as well as hippocampus-related cognitive tasks. RESULTS: We detected selective increases in phosphorylation of ribosomal protein S6 in interneurons, indicating cell-specific-upregulated mTORC1 signaling. At the behavioral level, Nkx2.1(Cre/wt);Tsc1(f/wt) mice exhibited intact contextual fear memory, but impaired contextual fear discrimination. They displayed intact spatial learning and reference memory but impairment in spatial working memory. Whole-cell recordings in hippocampal slices of Nkx2.1(Cre/wt);Tsc1(f/wt) mice showed intact basic membrane properties, as well as miniature excitatory and inhibitory synaptic transmission, in pyramidal and Nkx2.1-expressing inhibitory cells. Using optogenetic activation of Nkx2.1 interneurons in slices of Nkx2.1(Cre/wt);Tsc1(f/wt) mice, we found a decrease in synaptic inhibition of pyramidal cells. Chronic, but not acute treatment, with the mTORC1 inhibitor rapamycin reversed the impairment in synaptic inhibition. CONCLUSIONS: Our results indicate that Tsc1 haploinsufficiency in MGE-derived inhibitory cells upregulates mTORC1 activity in these interneurons, reduces their synaptic inhibition of pyramidal cells, and alters contextual fear discrimination and spatial working memory. Thus, selective dysregulation of mTORC1 function in Nkx2.1-expressing inhibitory cells appears sufficient to impair synaptic inhibition and contributes to cognitive deficits in the Tsc1 mouse model of TSC. En ligne : http://dx.doi.org/10.1186/s13229-020-00340-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study / Dorinde M. VAN ANDEL in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 30 p. Titre : Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study Type de document : Texte imprimé et/ou numérique Auteurs : Dorinde M. VAN ANDEL, Auteur ; Jan J. SPRENGERS, Auteur ; Bob ORANJE, Auteur ; Floor E. SCHEEPERS, Auteur ; Floor E. JANSEN, Auteur ; Hilgo BRUINING, Auteur Article en page(s) : 30 p. Langues : Anglais (eng) Mots-clés : Bumetanide  Erp  Irritability  NKCC1 antagonist  Neurocognitive task  Open-label  Tand  Tuberous sclerosis complex Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of ?-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC. METHODS: Participants were treated with bumetanide (2dd 0.5-1.0?mg) for 13?weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91?days of treatment and after a 28-day wash-out period. RESULTS: Fifteen patients (8-21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p = .001, d = .773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p = .002, d = .549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p = .003, d = .686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency. LIMITATIONS: The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures. CONCLUSIONS: Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016. En ligne : http://dx.doi.org/10.1186/s13229-020-00335-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study [Texte imprimé et/ou numérique] / Dorinde M. VAN ANDEL, Auteur ; Jan J. SPRENGERS, Auteur ; Bob ORANJE, Auteur ; Floor E. SCHEEPERS, Auteur ; Floor E. JANSEN, Auteur ; Hilgo BRUINING, Auteur . - 30 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 30 p. Mots-clés : Bumetanide  Erp  Irritability  NKCC1 antagonist  Neurocognitive task  Open-label  Tand  Tuberous sclerosis complex Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of ?-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC. METHODS: Participants were treated with bumetanide (2dd 0.5-1.0?mg) for 13?weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91?days of treatment and after a 28-day wash-out period. RESULTS: Fifteen patients (8-21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p = .001, d = .773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p = .002, d = .549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p = .003, d = .686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency. LIMITATIONS: The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures. CONCLUSIONS: Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016. En ligne : http://dx.doi.org/10.1186/s13229-020-00335-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Automated recognition of spontaneous facial expression in individuals with autism spectrum disorder: parsing response variability / Abigail BANGERTER in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 31 p. Titre : Automated recognition of spontaneous facial expression in individuals with autism spectrum disorder: parsing response variability Type de document : Texte imprimé et/ou numérique Auteurs : Abigail BANGERTER, Auteur ; Meenakshi CHATTERJEE, Auteur ; Joseph MANFREDONIA, Auteur ; Nikolay V. MANYAKOV, Auteur ; Seth NESS, Auteur ; Matthew A. BOICE, Auteur ; Andrew SKALKIN, Auteur ; Matthew S GOODWIN, Auteur ; Geraldine DAWSON, Auteur ; Robert HENDREN, Auteur ; Bennett L. LEVENTHAL, Auteur ; Frederick SHIC, Auteur ; Gahan PANDINA, Auteur Article en page(s) : 31 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Emotional regulation  Emotions  Facial expression  Impulsive behavior  LLC, and may hold company equity. AS was an employee of Janssen Research &  Development at the time of the study. MSG has received research and consulting  funding from Janssen Research & Development. GD is on the Scientific Advisory Boards  of Janssen Research & Development  Akili, Inc.  LabCorp, Inc.  and Roche  Pharmaceutical Company  is a consultant for Apple, Inc  Gerson Lehrman Group  Guidepoint, Inc.  and Axial Ventures  has received grant funding from Janssen  Research & Development  and is the CEO of DASIO, LLC. GD receives royalties from  Guilford Press, Springer, and Oxford University Press. RH received reimbursement for  consultation from Janssen Research & Development. BL has received research grant  funding from the NIH  is a consultant to Janssen Research & Development, the  Illinois Children’s Healthcare Foundation  and is a board member of the Brain  Research Foundation. FS is on the Scientific Advisory Board, is a consultant to and  received grant funding from Janssen Research & Development, and has also received  grant funding from Roche. Index. décimale : PER Périodiques Résumé : BACKGROUND: Reduction or differences in facial expression are a core diagnostic feature of autism spectrum disorder (ASD), yet evidence regarding the extent of this discrepancy is limited and inconsistent. Use of automated facial expression detection technology enables accurate and efficient tracking of facial expressions that has potential to identify individual response differences. METHODS: Children and adults with ASD (N = 124) and typically developing (TD, N = 41) were shown short clips of "funny videos." Using automated facial analysis software, we investigated differences between ASD and TD groups and within the ASD group in evidence of facial action unit (AU) activation related to the expression of positive facial expression, in particular, a smile. RESULTS: Individuals with ASD on average showed less evidence of facial AUs (AU12, AU6) relating to positive facial expression, compared to the TD group (p < .05, r = -?0.17). Using Gaussian mixture model for clustering, we identified two distinct distributions within the ASD group, which were then compared to the TD group. One subgroup (n = 35), termed "over-responsive," expressed more intense positive facial expressions in response to the videos than the TD group (p < .001, r = 0.31). The second subgroup (n = 89), ("under-responsive"), displayed fewer, less intense positive facial expressions in response to videos than the TD group (p < .001; r = -?0.36). The over-responsive subgroup differed from the under-responsive subgroup in age and caregiver-reported impulsivity (p < .05, r = 0.21). Reduced expression in the under-responsive, but not the over-responsive group, was related to caregiver-reported social withdrawal (p < .01, r = -?0.3). LIMITATIONS: This exploratory study does not account for multiple comparisons, and future work will have to ascertain the strength and reproducibility of all results. Reduced displays of positive facial expressions do not mean individuals with ASD do not experience positive emotions. CONCLUSIONS: Individuals with ASD differed from the TD group in their facial expressions of positive emotion in response to "funny videos." Identification of subgroups based on response may help in parsing heterogeneity in ASD and enable targeting of treatment based on subtypes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299700. Registration date: November 24, 2014. En ligne : http://dx.doi.org/10.1186/s13229-020-00327-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Automated recognition of spontaneous facial expression in individuals with autism spectrum disorder: parsing response variability [Texte imprimé et/ou numérique] / Abigail BANGERTER, Auteur ; Meenakshi CHATTERJEE, Auteur ; Joseph MANFREDONIA, Auteur ; Nikolay V. MANYAKOV, Auteur ; Seth NESS, Auteur ; Matthew A. BOICE, Auteur ; Andrew SKALKIN, Auteur ; Matthew S GOODWIN, Auteur ; Geraldine DAWSON, Auteur ; Robert HENDREN, Auteur ; Bennett L. LEVENTHAL, Auteur ; Frederick SHIC, Auteur ; Gahan PANDINA, Auteur . - 31 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 31 p. Mots-clés : Autism spectrum disorder  Emotional regulation  Emotions  Facial expression  Impulsive behavior  LLC, and may hold company equity. AS was an employee of Janssen Research &  Development at the time of the study. MSG has received research and consulting  funding from Janssen Research & Development. GD is on the Scientific Advisory Boards  of Janssen Research & Development  Akili, Inc.  LabCorp, Inc.  and Roche  Pharmaceutical Company  is a consultant for Apple, Inc  Gerson Lehrman Group  Guidepoint, Inc.  and Axial Ventures  has received grant funding from Janssen  Research & Development  and is the CEO of DASIO, LLC. GD receives royalties from  Guilford Press, Springer, and Oxford University Press. RH received reimbursement for  consultation from Janssen Research & Development. BL has received research grant  funding from the NIH  is a consultant to Janssen Research & Development, the  Illinois Children’s Healthcare Foundation  and is a board member of the Brain  Research Foundation. FS is on the Scientific Advisory Board, is a consultant to and  received grant funding from Janssen Research & Development, and has also received  grant funding from Roche. Index. décimale : PER Périodiques Résumé : BACKGROUND: Reduction or differences in facial expression are a core diagnostic feature of autism spectrum disorder (ASD), yet evidence regarding the extent of this discrepancy is limited and inconsistent. Use of automated facial expression detection technology enables accurate and efficient tracking of facial expressions that has potential to identify individual response differences. METHODS: Children and adults with ASD (N = 124) and typically developing (TD, N = 41) were shown short clips of "funny videos." Using automated facial analysis software, we investigated differences between ASD and TD groups and within the ASD group in evidence of facial action unit (AU) activation related to the expression of positive facial expression, in particular, a smile. RESULTS: Individuals with ASD on average showed less evidence of facial AUs (AU12, AU6) relating to positive facial expression, compared to the TD group (p < .05, r = -?0.17). Using Gaussian mixture model for clustering, we identified two distinct distributions within the ASD group, which were then compared to the TD group. One subgroup (n = 35), termed "over-responsive," expressed more intense positive facial expressions in response to the videos than the TD group (p < .001, r = 0.31). The second subgroup (n = 89), ("under-responsive"), displayed fewer, less intense positive facial expressions in response to videos than the TD group (p < .001; r = -?0.36). The over-responsive subgroup differed from the under-responsive subgroup in age and caregiver-reported impulsivity (p < .05, r = 0.21). Reduced expression in the under-responsive, but not the over-responsive group, was related to caregiver-reported social withdrawal (p < .01, r = -?0.3). LIMITATIONS: This exploratory study does not account for multiple comparisons, and future work will have to ascertain the strength and reproducibility of all results. Reduced displays of positive facial expressions do not mean individuals with ASD do not experience positive emotions. CONCLUSIONS: Individuals with ASD differed from the TD group in their facial expressions of positive emotion in response to "funny videos." Identification of subgroups based on response may help in parsing heterogeneity in ASD and enable targeting of treatment based on subtypes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299700. Registration date: November 24, 2014. En ligne : http://dx.doi.org/10.1186/s13229-020-00327-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD / Lorenza CULOTTA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 32 p. Titre : Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD Type de document : Texte imprimé et/ou numérique Auteurs : Lorenza CULOTTA, Auteur ; Peter PENZES, Auteur Article en page(s) : 32 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Excitation/inhibition balance  Induced pluripotent stem cell Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and repetitive or restricted behaviors. ASD subjects exhibit complex genetic and clinical heterogeneity, thus hindering the discovery of pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity, one hypothesis that has emerged is that ASD arises from a disruption of the neuronal network activity due to perturbation of the synaptic excitation and inhibition (E/I) balance. The development of induced pluripotent stem cell (iPSC) technology and recent advances in neuronal differentiation techniques provide a unique opportunity to model complex neuronal connectivity and to test the E/I hypothesis of ASD in human-based models. Here, we aim to review the latest advances in studying the different cellular and molecular mechanisms contributing to E/I balance using iPSC-based in vitro models of ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00339-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD [Texte imprimé et/ou numérique] / Lorenza CULOTTA, Auteur ; Peter PENZES, Auteur . - 32 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 32 p. Mots-clés : Autism spectrum disorder  Excitation/inhibition balance  Induced pluripotent stem cell Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and repetitive or restricted behaviors. ASD subjects exhibit complex genetic and clinical heterogeneity, thus hindering the discovery of pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity, one hypothesis that has emerged is that ASD arises from a disruption of the neuronal network activity due to perturbation of the synaptic excitation and inhibition (E/I) balance. The development of induced pluripotent stem cell (iPSC) technology and recent advances in neuronal differentiation techniques provide a unique opportunity to model complex neuronal connectivity and to test the E/I hypothesis of ASD in human-based models. Here, we aim to review the latest advances in studying the different cellular and molecular mechanisms contributing to E/I balance using iPSC-based in vitro models of ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00339-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Modeling neuronal consequences of autism-associated gene regulatory variants with human induced pluripotent stem cells / P. Joel ROSS in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 33 p. Titre : Modeling neuronal consequences of autism-associated gene regulatory variants with human induced pluripotent stem cells Type de document : Texte imprimé et/ou numérique Auteurs : P. Joel ROSS, Auteur ; Rebecca S. F. MOK, Auteur ; Brandon S. SMITH, Auteur ; Deivid C. RODRIGUES, Auteur ; Marat MUFTEEV, Auteur ; Stephen SCHERER, Auteur ; James ELLIS, Auteur Article en page(s) : 33 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Genetic factors contribute to the development of autism spectrum disorder (ASD), and although non-protein-coding regions of the genome are being increasingly implicated in ASD, the functional consequences of these variants remain largely uncharacterized. Induced pluripotent stem cells (iPSCs) enable the production of personalized neurons that are genetically matched to people with ASD and can therefore be used to directly test the effects of genomic variation on neuronal gene expression, synapse function, and connectivity. The combined use of human pluripotent stem cells with genome editing to introduce or correct specific variants has proved to be a powerful approach for exploring the functional consequences of ASD-associated variants in protein-coding genes and, more recently, long non-coding RNAs (lncRNAs). Here, we review recent studies that implicate lncRNAs, other non-coding mutations, and regulatory variants in ASD susceptibility. We also discuss experimental design considerations for using iPSCs and genome editing to study the role of the non-protein-coding genome in ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00333-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Modeling neuronal consequences of autism-associated gene regulatory variants with human induced pluripotent stem cells [Texte imprimé et/ou numérique] / P. Joel ROSS, Auteur ; Rebecca S. F. MOK, Auteur ; Brandon S. SMITH, Auteur ; Deivid C. RODRIGUES, Auteur ; Marat MUFTEEV, Auteur ; Stephen SCHERER, Auteur ; James ELLIS, Auteur . - 33 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 33 p. Index. décimale : PER Périodiques Résumé : Genetic factors contribute to the development of autism spectrum disorder (ASD), and although non-protein-coding regions of the genome are being increasingly implicated in ASD, the functional consequences of these variants remain largely uncharacterized. Induced pluripotent stem cells (iPSCs) enable the production of personalized neurons that are genetically matched to people with ASD and can therefore be used to directly test the effects of genomic variation on neuronal gene expression, synapse function, and connectivity. The combined use of human pluripotent stem cells with genome editing to introduce or correct specific variants has proved to be a powerful approach for exploring the functional consequences of ASD-associated variants in protein-coding genes and, more recently, long non-coding RNAs (lncRNAs). Here, we review recent studies that implicate lncRNAs, other non-coding mutations, and regulatory variants in ASD susceptibility. We also discuss experimental design considerations for using iPSCs and genome editing to study the role of the non-protein-coding genome in ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00333-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Effectiveness of a modified group cognitive behavioral therapy program for anxiety in children with ASD delivered in a community context / Abbie SOLISH in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 34 p. Titre : Effectiveness of a modified group cognitive behavioral therapy program for anxiety in children with ASD delivered in a community context Type de document : Texte imprimé et/ou numérique Auteurs : Abbie SOLISH, Auteur ; Nora KLEMENCIC, Auteur ; Anne RITZEMA, Auteur ; Vicki NOLAN, Auteur ; Martha PILKINGTON, Auteur ; Evdokia ANAGNOSTOU, Auteur ; Jessica BRIAN, Auteur Article en page(s) : 34 p. Langues : Anglais (eng) Mots-clés : Anxiety  Autism  Autism spectrum disorder  Cognitive behavioral therapy  Community  Group  Implementation  Intervention Index. décimale : PER Périodiques Résumé : BACKGROUND: Youth with autism spectrum disorder (ASD) experience high rates (approximately 50-79%) of comorbid anxiety problems. Given the significant interference and distress that excessive anxiety can cause, evidence-based intervention is necessary in order to reduce long-term negative effects. Cognitive behavioral therapy (CBT) has demonstrated efficacy for treating anxiety disorders across the lifespan, both in individual and group formats. Recently, modified CBT programs for youth with ASD have been developed, showing positive outcomes. To date, these modified CBT programs have primarily been evaluated in controlled research settings. METHODS: The current community effectiveness study investigated the effectiveness of a modified group CBT program (Facing Your Fears) delivered in a tertiary care hospital and across six community-based agencies providing services for youth with ASD. Data were collected over six years (N = 105 youth with ASD; ages 6-15 years). RESULTS: Hospital and community samples did not differ significantly, except in terms of age (hospital M = 10.08 years; community M = 10.87 years). Results indicated significant improvements in anxiety levels from baseline to post-treatment across measures, with medium effect sizes. An attempt to uncover individual characteristics that predict response to treatment was unsuccessful. CONCLUSIONS: Overall, this study demonstrated that community implementation of a modified group CBT program for youth with ASD is feasible and effective for treating elevated anxiety. En ligne : http://dx.doi.org/10.1186/s13229-020-00341-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Effectiveness of a modified group cognitive behavioral therapy program for anxiety in children with ASD delivered in a community context [Texte imprimé et/ou numérique] / Abbie SOLISH, Auteur ; Nora KLEMENCIC, Auteur ; Anne RITZEMA, Auteur ; Vicki NOLAN, Auteur ; Martha PILKINGTON, Auteur ; Evdokia ANAGNOSTOU, Auteur ; Jessica BRIAN, Auteur . - 34 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 34 p. Mots-clés : Anxiety  Autism  Autism spectrum disorder  Cognitive behavioral therapy  Community  Group  Implementation  Intervention Index. décimale : PER Périodiques Résumé : BACKGROUND: Youth with autism spectrum disorder (ASD) experience high rates (approximately 50-79%) of comorbid anxiety problems. Given the significant interference and distress that excessive anxiety can cause, evidence-based intervention is necessary in order to reduce long-term negative effects. Cognitive behavioral therapy (CBT) has demonstrated efficacy for treating anxiety disorders across the lifespan, both in individual and group formats. Recently, modified CBT programs for youth with ASD have been developed, showing positive outcomes. To date, these modified CBT programs have primarily been evaluated in controlled research settings. METHODS: The current community effectiveness study investigated the effectiveness of a modified group CBT program (Facing Your Fears) delivered in a tertiary care hospital and across six community-based agencies providing services for youth with ASD. Data were collected over six years (N = 105 youth with ASD; ages 6-15 years). RESULTS: Hospital and community samples did not differ significantly, except in terms of age (hospital M = 10.08 years; community M = 10.87 years). Results indicated significant improvements in anxiety levels from baseline to post-treatment across measures, with medium effect sizes. An attempt to uncover individual characteristics that predict response to treatment was unsuccessful. CONCLUSIONS: Overall, this study demonstrated that community implementation of a modified group CBT program for youth with ASD is feasible and effective for treating elevated anxiety. En ligne : http://dx.doi.org/10.1186/s13229-020-00341-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Prevalence and cumulative incidence of autism spectrum disorders and the patterns of co-occurring neurodevelopmental disorders in a total population sample of 5-year-old children / Manabu SAITO in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 35 p. Titre : Prevalence and cumulative incidence of autism spectrum disorders and the patterns of co-occurring neurodevelopmental disorders in a total population sample of 5-year-old children Type de document : Texte imprimé et/ou numérique Auteurs : Manabu SAITO, Auteur ; Tomoya HIROTA, Auteur ; Yui SAKAMOTO, Auteur ; Masaki ADACHI, Auteur ; Michio TAKAHASHI, Auteur ; Ayako OSATO-KANEDA, Auteur ; Young Shin KIM, Auteur ; Bennett L. LEVENTHAL, Auteur ; Amy SHUI, Auteur ; Sumi KATO, Auteur ; Kazuhiko NAKAMURA, Auteur Article en page(s) : 35 p. Langues : Anglais (eng) Mots-clés : A total population study  Autism spectrum disorder  Co-existing neurodevelopmental disorders  Cumulative incidence  Prevalence Index. décimale : PER Périodiques Résumé : BACKGROUNDS: Whether there is a true increase in autism spectrum disorder (ASD) frequency or not remains unclear. Additionally, the rates of co-existing neurodevelopmental disorders (NDD) in a total population sample has not been fully examined before. Therefore, using a total population sample in Japan, we aimed to estimate the prevalence and cumulative incidence of autism spectrum disorder (ASD) annually, to determine whether there is a true increase in ASD prevalence by estimating the cumulative incidence of ASD annually, and to examine the rates of co-existing neurodevelopmental disorders (NDD). METHOD: In this cross-sectional sequential design study, all 5-year-old children in the catchment area underwent the screening annually from the year 2013-2016. Screen-positive children were invited to participate in a comprehensive assessment, including child and parent interview, behavioral observation, and cognitive and motor function testing. All cases were reviewed by a multidisciplinary research team. RESULTS: Caregivers of 3954 children returned the screening, among which 559 children underwent the assessment with 87 children receiving an ASD diagnosis. Adjusted ASD prevalence was 3.22% (95% confidence interval (CI) 2.66-3.76%). The male to female ratio of the crude prevalence was 2.2:1. The cumulative incidence of ASD up to 5?years of age for the total study years was 1.31% (95% CI 1.00-1.62%). A generalized linear model revealed no significant linear trends in 5-year cumulative incidence over the study years. Only 11.5% of children had ASD alone; the remaining 88.5% were found to have at least one co-existing NDD. LIMITATIONS: Modest sample size for a total population study. CONCLUSIONS: Our findings demonstrate the stability of the 5-year cumulative incidence of ASD, implying no true rise in ASD incident cases over the 4-year study period in the study catchment area. High rates of co-existing NDDs reflect the importance of investigating broad developmental challenges in children with ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00342-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Prevalence and cumulative incidence of autism spectrum disorders and the patterns of co-occurring neurodevelopmental disorders in a total population sample of 5-year-old children [Texte imprimé et/ou numérique] / Manabu SAITO, Auteur ; Tomoya HIROTA, Auteur ; Yui SAKAMOTO, Auteur ; Masaki ADACHI, Auteur ; Michio TAKAHASHI, Auteur ; Ayako OSATO-KANEDA, Auteur ; Young Shin KIM, Auteur ; Bennett L. LEVENTHAL, Auteur ; Amy SHUI, Auteur ; Sumi KATO, Auteur ; Kazuhiko NAKAMURA, Auteur . - 35 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 35 p. Mots-clés : A total population study  Autism spectrum disorder  Co-existing neurodevelopmental disorders  Cumulative incidence  Prevalence Index. décimale : PER Périodiques Résumé : BACKGROUNDS: Whether there is a true increase in autism spectrum disorder (ASD) frequency or not remains unclear. Additionally, the rates of co-existing neurodevelopmental disorders (NDD) in a total population sample has not been fully examined before. Therefore, using a total population sample in Japan, we aimed to estimate the prevalence and cumulative incidence of autism spectrum disorder (ASD) annually, to determine whether there is a true increase in ASD prevalence by estimating the cumulative incidence of ASD annually, and to examine the rates of co-existing neurodevelopmental disorders (NDD). METHOD: In this cross-sectional sequential design study, all 5-year-old children in the catchment area underwent the screening annually from the year 2013-2016. Screen-positive children were invited to participate in a comprehensive assessment, including child and parent interview, behavioral observation, and cognitive and motor function testing. All cases were reviewed by a multidisciplinary research team. RESULTS: Caregivers of 3954 children returned the screening, among which 559 children underwent the assessment with 87 children receiving an ASD diagnosis. Adjusted ASD prevalence was 3.22% (95% confidence interval (CI) 2.66-3.76%). The male to female ratio of the crude prevalence was 2.2:1. The cumulative incidence of ASD up to 5?years of age for the total study years was 1.31% (95% CI 1.00-1.62%). A generalized linear model revealed no significant linear trends in 5-year cumulative incidence over the study years. Only 11.5% of children had ASD alone; the remaining 88.5% were found to have at least one co-existing NDD. LIMITATIONS: Modest sample size for a total population study. CONCLUSIONS: Our findings demonstrate the stability of the 5-year cumulative incidence of ASD, implying no true rise in ASD incident cases over the 4-year study period in the study catchment area. High rates of co-existing NDDs reflect the importance of investigating broad developmental challenges in children with ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00342-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Age-related differences in white matter diffusion measures in autism spectrum condition / Abigail THOMPSON in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 36 p. Titre : Age-related differences in white matter diffusion measures in autism spectrum condition Type de document : Texte imprimé et/ou numérique Auteurs : Abigail THOMPSON, Auteur ; Asal SHAHIDIANI, Auteur ; Anne FRITZ, Auteur ; Jonathan O'MUIRCHEARTAIGH, Auteur ; Lindsay WALKER, Auteur ; Vera D'ALMEIDA, Auteur ; Clodagh M. MURPHY, Auteur ; Eileen DALY, Auteur ; Declan MURPHY, Auteur ; Steve WILLIAMS, Auteur ; Sean DEONI, Auteur ; Christine ECKER, Auteur Article en page(s) : 36 p. Langues : Anglais (eng) Mots-clés : Autism  Connectivity  Diffusion weighted imaging  Tract-based spatial statistics Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum condition (ASC) is accompanied by developmental differences in brain anatomy and connectivity. White matter differences in ASC have been widely studied with diffusion imaging but results are heterogeneous and vary across the age range of study participants and varying methodological approaches. To characterize the neurodevelopmental trajectory of white matter maturation, it is necessary to examine a broad age range of individuals on the autism spectrum and typically developing controls, and investigate age × group interactions. METHODS: Here, we employed a spatially unbiased tract-based spatial statistics (TBSS) approach to examine age-related differences in white matter connectivity in a sample of 41 individuals with ASC, and 41 matched controls between 7-17 years of age. RESULTS: We found significant age-related differences between the ASC and control group in widespread brain regions. This included age-related differences in the uncinate fasciculus, corticospinal tract, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior longitudinal fasciculus and forceps major. Measures of fractional anisotropy (FA) were significantly positively associated with age in both groups. However, this relationship was significantly stronger in the ASC group relative to controls. Measures of radial diffusivity (RD) were significantly negatively associated with age in both groups, but this relationship was significantly stronger in the ASC group relative to controls. LIMITATIONS: The generalisability of our findings is limited by the restriction of the sample to right-handed males with an IQ > 70. Furthermore, a longitudinal design would be required to fully investigate maturational processes across this age group. CONCLUSIONS: Taken together, our findings suggest that autistic males have an altered trajectory of white matter maturation relative to controls. Future longitudinal analyses are required to further characterize the extent and time course of these differences. En ligne : http://dx.doi.org/10.1186/s13229-020-00325-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Age-related differences in white matter diffusion measures in autism spectrum condition [Texte imprimé et/ou numérique] / Abigail THOMPSON, Auteur ; Asal SHAHIDIANI, Auteur ; Anne FRITZ, Auteur ; Jonathan O'MUIRCHEARTAIGH, Auteur ; Lindsay WALKER, Auteur ; Vera D'ALMEIDA, Auteur ; Clodagh M. MURPHY, Auteur ; Eileen DALY, Auteur ; Declan MURPHY, Auteur ; Steve WILLIAMS, Auteur ; Sean DEONI, Auteur ; Christine ECKER, Auteur . - 36 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 36 p. Mots-clés : Autism  Connectivity  Diffusion weighted imaging  Tract-based spatial statistics Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum condition (ASC) is accompanied by developmental differences in brain anatomy and connectivity. White matter differences in ASC have been widely studied with diffusion imaging but results are heterogeneous and vary across the age range of study participants and varying methodological approaches. To characterize the neurodevelopmental trajectory of white matter maturation, it is necessary to examine a broad age range of individuals on the autism spectrum and typically developing controls, and investigate age × group interactions. METHODS: Here, we employed a spatially unbiased tract-based spatial statistics (TBSS) approach to examine age-related differences in white matter connectivity in a sample of 41 individuals with ASC, and 41 matched controls between 7-17 years of age. RESULTS: We found significant age-related differences between the ASC and control group in widespread brain regions. This included age-related differences in the uncinate fasciculus, corticospinal tract, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior longitudinal fasciculus and forceps major. Measures of fractional anisotropy (FA) were significantly positively associated with age in both groups. However, this relationship was significantly stronger in the ASC group relative to controls. Measures of radial diffusivity (RD) were significantly negatively associated with age in both groups, but this relationship was significantly stronger in the ASC group relative to controls. LIMITATIONS: The generalisability of our findings is limited by the restriction of the sample to right-handed males with an IQ > 70. Furthermore, a longitudinal design would be required to fully investigate maturational processes across this age group. CONCLUSIONS: Taken together, our findings suggest that autistic males have an altered trajectory of white matter maturation relative to controls. Future longitudinal analyses are required to further characterize the extent and time course of these differences. En ligne : http://dx.doi.org/10.1186/s13229-020-00325-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Cell therapy approaches to autism: a review of clinical trial data / Jack PRICE in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 37 p. Titre : Cell therapy approaches to autism: a review of clinical trial data Type de document : Texte imprimé et/ou numérique Auteurs : Jack PRICE, Auteur Article en page(s) : 37 p. Langues : Anglais (eng) Mots-clés : Autism  Cell therapy  Clinical trials  Stem cells Index. décimale : PER Périodiques Résumé : A number of clinical trials of cell therapies for autism spectrum disorder have been conducted, and some have published their outcomes. This review considers the data that have emerged from this small set of published trials, evaluates their success, and proposes further steps that could be taken if this field of endeavour is to be pursued further. A number of reservations arise from this tranche of studies, specifically the absence of identified therapeutic targets, and deficiencies in the therapeutic approach that is being employed. If this therapeutic direction is to be pursued further, then additional pre-clinical studies are recommended that might lead to improvements in patient stratification, biomarkers, the defined mode of action, and the preparation and identification of the therapeutic cells themselves. En ligne : http://dx.doi.org/10.1186/s13229-020-00348-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Cell therapy approaches to autism: a review of clinical trial data [Texte imprimé et/ou numérique] / Jack PRICE, Auteur . - 37 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 37 p. Mots-clés : Autism  Cell therapy  Clinical trials  Stem cells Index. décimale : PER Périodiques Résumé : A number of clinical trials of cell therapies for autism spectrum disorder have been conducted, and some have published their outcomes. This review considers the data that have emerged from this small set of published trials, evaluates their success, and proposes further steps that could be taken if this field of endeavour is to be pursued further. A number of reservations arise from this tranche of studies, specifically the absence of identified therapeutic targets, and deficiencies in the therapeutic approach that is being employed. If this therapeutic direction is to be pursued further, then additional pre-clinical studies are recommended that might lead to improvements in patient stratification, biomarkers, the defined mode of action, and the preparation and identification of the therapeutic cells themselves. En ligne : http://dx.doi.org/10.1186/s13229-020-00348-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Identification of amygdala-expressed genes associated with autism spectrum disorder / Maria Jesus HERRERO in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 39 p. Titre : Identification of amygdala-expressed genes associated with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Maria Jesus HERRERO, Auteur ; Dmitry VELMESHEV, Auteur ; David HERNANDEZ-PINEDA, Auteur ; Saarthak SETHI, Auteur ; Shawn SORRELLS, Auteur ; Payal BANERJEE, Auteur ; Catherine SULLIVAN, Auteur ; Abha R. GUPTA, Auteur ; Arnold R. KRIEGSTEIN, Auteur ; Joshua G. CORBIN, Auteur Article en page(s) : 39 p. Langues : Anglais (eng) Mots-clés : ASD genes  Amygdala  Autism spectrum disorder  Brain development  Single nucleus RNA sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. METHODS: Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20?years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. RESULTS: Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. LIMITATIONS: We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. CONCLUSIONS: Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala. En ligne : http://dx.doi.org/10.1186/s13229-020-00346-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Identification of amygdala-expressed genes associated with autism spectrum disorder [Texte imprimé et/ou numérique] / Maria Jesus HERRERO, Auteur ; Dmitry VELMESHEV, Auteur ; David HERNANDEZ-PINEDA, Auteur ; Saarthak SETHI, Auteur ; Shawn SORRELLS, Auteur ; Payal BANERJEE, Auteur ; Catherine SULLIVAN, Auteur ; Abha R. GUPTA, Auteur ; Arnold R. KRIEGSTEIN, Auteur ; Joshua G. CORBIN, Auteur . - 39 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 39 p. Mots-clés : ASD genes  Amygdala  Autism spectrum disorder  Brain development  Single nucleus RNA sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. METHODS: Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20?years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. RESULTS: Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. LIMITATIONS: We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. CONCLUSIONS: Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala. En ligne : http://dx.doi.org/10.1186/s13229-020-00346-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Dysregulation of protein synthesis and dendritic spine morphogenesis in ASD: studies in human pluripotent stem cells / Louisa Hoi-Ying LO in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 40 p. Titre : Dysregulation of protein synthesis and dendritic spine morphogenesis in ASD: studies in human pluripotent stem cells Type de document : Texte imprimé et/ou numérique Auteurs : Louisa Hoi-Ying LO, Auteur ; Kwok-On LAI, Auteur Article en page(s) : 40 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a brain disorder that involves changes in neuronal connections. Abnormal morphology of dendritic spines on postsynaptic neurons has been observed in ASD patients and transgenic mice that model different monogenetic causes of ASD. A number of ASD-associated genetic variants are known to disrupt dendritic local protein synthesis, which is essential for spine morphogenesis, synaptic transmission, and plasticity. Most of our understanding on the molecular mechanism underlying ASD depends on studies using rodents. However, recent advance in human pluripotent stem cells and their neural differentiation provides a powerful alternative tool to understand the cellular aspects of human neurological disorders. In this review, we summarize recent progress on studying mRNA targeting and local protein synthesis in stem cell-derived neurons, and discuss how perturbation of these processes may impact synapse development and functions that are relevant to cognitive deficits in ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00349-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Dysregulation of protein synthesis and dendritic spine morphogenesis in ASD: studies in human pluripotent stem cells [Texte imprimé et/ou numérique] / Louisa Hoi-Ying LO, Auteur ; Kwok-On LAI, Auteur . - 40 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 40 p. Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a brain disorder that involves changes in neuronal connections. Abnormal morphology of dendritic spines on postsynaptic neurons has been observed in ASD patients and transgenic mice that model different monogenetic causes of ASD. A number of ASD-associated genetic variants are known to disrupt dendritic local protein synthesis, which is essential for spine morphogenesis, synaptic transmission, and plasticity. Most of our understanding on the molecular mechanism underlying ASD depends on studies using rodents. However, recent advance in human pluripotent stem cells and their neural differentiation provides a powerful alternative tool to understand the cellular aspects of human neurological disorders. In this review, we summarize recent progress on studying mRNA targeting and local protein synthesis in stem cell-derived neurons, and discuss how perturbation of these processes may impact synapse development and functions that are relevant to cognitive deficits in ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00349-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment / Kagistia Hana UTAMI in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 41 p. Titre : Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment Type de document : Texte imprimé et/ou numérique Auteurs : Kagistia Hana UTAMI, Auteur ; Nur Amirah Binte Mohammad YUSOF, Auteur ; Jing Eugene KWA, Auteur ; Ulla-Kaisa PETERI, Auteur ; Maija L. CASTRÉN, Auteur ; Mahmoud A. POULADI, Auteur Article en page(s) : 41 p. Langues : Anglais (eng) Mots-clés : Fragile X syndrome  Human stem cells  Protein synthesis  Therapy  interest. Index. décimale : PER Périodiques Résumé : FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS. En ligne : http://dx.doi.org/10.1186/s13229-020-00350-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment [Texte imprimé et/ou numérique] / Kagistia Hana UTAMI, Auteur ; Nur Amirah Binte Mohammad YUSOF, Auteur ; Jing Eugene KWA, Auteur ; Ulla-Kaisa PETERI, Auteur ; Maija L. CASTRÉN, Auteur ; Mahmoud A. POULADI, Auteur . - 41 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 41 p. Mots-clés : Fragile X syndrome  Human stem cells  Protein synthesis  Therapy  interest. Index. décimale : PER Périodiques Résumé : FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS. En ligne : http://dx.doi.org/10.1186/s13229-020-00350-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors / Suzy VARDERIDOU-MINASIAN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 38 p. Titre : Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors Type de document : Texte imprimé et/ou numérique Auteurs : Suzy VARDERIDOU-MINASIAN, Auteur ; Lisa HINZ, Auteur ; Dominique HAGEMANS, Auteur ; Daniëlle POSTHUMA, Auteur ; Maarten ALTELAAR, Auteur ; Vivi M. HEINE, Auteur Article en page(s) : 38 p. Langues : Anglais (eng) Mots-clés : Neuron differentiation  Quantitative mass spectrometry  Rett syndrome  TMT-10plex  iPSC Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages. METHODS: To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. RESULTS: We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed. LIMITATIONS: The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms. CONCLUSIONS: During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3-4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome. En ligne : http://dx.doi.org/10.1186/s13229-020-00344-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors [Texte imprimé et/ou numérique] / Suzy VARDERIDOU-MINASIAN, Auteur ; Lisa HINZ, Auteur ; Dominique HAGEMANS, Auteur ; Daniëlle POSTHUMA, Auteur ; Maarten ALTELAAR, Auteur ; Vivi M. HEINE, Auteur . - 38 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 38 p. Mots-clés : Neuron differentiation  Quantitative mass spectrometry  Rett syndrome  TMT-10plex  iPSC Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages. METHODS: To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. RESULTS: We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed. LIMITATIONS: The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms. CONCLUSIONS: During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3-4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome. En ligne : http://dx.doi.org/10.1186/s13229-020-00344-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD / Danijela DRAKULIC in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 42 p. Titre : Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD Type de document : Texte imprimé et/ou numérique Auteurs : Danijela DRAKULIC, Auteur ; Srdjan DJUROVIC, Auteur ; Yasir Ahmed SYED, Auteur ; Sebastiano TRATTARO, Auteur ; Nicolò CAPORALE, Auteur ; Anna FALK, Auteur ; Rivka OFIR, Auteur ; Vivi M. HEINE, Auteur ; Samuel J. R. A. CHAWNER, Auteur ; Antonio RODRIGUEZ-MORENO, Auteur ; Marianne B. M. VAN DEN BREE, Auteur ; Giuseppe TESTA, Auteur ; Spyros PETRAKIS, Auteur ; Adrian J. HARWOOD, Auteur Article en page(s) : 42 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders (ASD)  Copy number variants (CNVs)  Human iPSCs  Neurodevelopmental disorders (NDD) Index. décimale : PER Périodiques Résumé : Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets. En ligne : http://dx.doi.org/10.1186/s13229-020-00343-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD [Texte imprimé et/ou numérique] / Danijela DRAKULIC, Auteur ; Srdjan DJUROVIC, Auteur ; Yasir Ahmed SYED, Auteur ; Sebastiano TRATTARO, Auteur ; Nicolò CAPORALE, Auteur ; Anna FALK, Auteur ; Rivka OFIR, Auteur ; Vivi M. HEINE, Auteur ; Samuel J. R. A. CHAWNER, Auteur ; Antonio RODRIGUEZ-MORENO, Auteur ; Marianne B. M. VAN DEN BREE, Auteur ; Giuseppe TESTA, Auteur ; Spyros PETRAKIS, Auteur ; Adrian J. HARWOOD, Auteur . - 42 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 42 p. Mots-clés : Autism spectrum disorders (ASD)  Copy number variants (CNVs)  Human iPSCs  Neurodevelopmental disorders (NDD) Index. décimale : PER Périodiques Résumé : Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets. En ligne : http://dx.doi.org/10.1186/s13229-020-00343-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation / Shin Chung KANG in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 43 p. Titre : Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation Type de document : Texte imprimé et/ou numérique Auteurs : Shin Chung KANG, Auteur ; Ritika JAINI, Auteur ; Masahiro HITOMI, Auteur ; Hyunpil LEE, Auteur ; Nick SARN, Auteur ; Stetson THACKER, Auteur ; Charis ENG, Auteur Article en page(s) : 43 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Creb activation  Neural development  Neural stem cells  Neuronal maturation  PTEN mutation Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN, a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between PTEN and ASD and ensuing studies, we continue to have a limited understanding of how PTEN disruption drives ASD pathogenesis and maintenance. METHODS: We derived neural stem cells (NSCs) from the dentate gyrus (DG) of Pten(m3m4) mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in Pten(m3m4) NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR. RESULTS: The m3m4 mutation decreases Pten localization to the nucleus and its global expression over time. Pten(m3m4) NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of Pten(m3m4) NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some Pten(m3m4) glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in Pten(m3m4/m3m4) NSCs. We specifically observed loss of Creb phosphorylation at S133 in Pten(m3m4/m3m4) NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in Pten(m3m4/m3m4) NSCs. CONCLUSIONS: Constitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis. En ligne : http://dx.doi.org/10.1186/s13229-020-00337-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation [Texte imprimé et/ou numérique] / Shin Chung KANG, Auteur ; Ritika JAINI, Auteur ; Masahiro HITOMI, Auteur ; Hyunpil LEE, Auteur ; Nick SARN, Auteur ; Stetson THACKER, Auteur ; Charis ENG, Auteur . - 43 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 43 p. Mots-clés : Autism spectrum disorder  Creb activation  Neural development  Neural stem cells  Neuronal maturation  PTEN mutation Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN, a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between PTEN and ASD and ensuing studies, we continue to have a limited understanding of how PTEN disruption drives ASD pathogenesis and maintenance. METHODS: We derived neural stem cells (NSCs) from the dentate gyrus (DG) of Pten(m3m4) mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in Pten(m3m4) NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR. RESULTS: The m3m4 mutation decreases Pten localization to the nucleus and its global expression over time. Pten(m3m4) NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of Pten(m3m4) NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some Pten(m3m4) glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in Pten(m3m4/m3m4) NSCs. We specifically observed loss of Creb phosphorylation at S133 in Pten(m3m4/m3m4) NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in Pten(m3m4/m3m4) NSCs. CONCLUSIONS: Constitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis. En ligne : http://dx.doi.org/10.1186/s13229-020-00337-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Electronic communication in autism spectrum conditions / Lucy Anne LIVINGSTON in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 44 p. Titre : Electronic communication in autism spectrum conditions Type de document : Texte imprimé et/ou numérique Auteurs : Lucy Anne LIVINGSTON, Auteur ; Chris ASHWIN, Auteur ; Punit SHAH, Auteur Article en page(s) : 44 p. Langues : Anglais (eng) Mots-clés : Autism  Diagnosis  E-mail  Human computer interaction  Social communication Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1186/s13229-020-00329-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Electronic communication in autism spectrum conditions [Texte imprimé et/ou numérique] / Lucy Anne LIVINGSTON, Auteur ; Chris ASHWIN, Auteur ; Punit SHAH, Auteur . - 44 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 44 p. Mots-clés : Autism  Diagnosis  E-mail  Human computer interaction  Social communication Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1186/s13229-020-00329-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons / Catarina M. SEABRA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 45 p. Titre : Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : Catarina M. SEABRA, Auteur ; Tatsiana ANEICHYK, Auteur ; Serkan ERDIN, Auteur ; Derek J. C. TAI, Auteur ; Celine E. F. DE ESCH, Auteur ; Parisa RAZAZ, Auteur ; Yu AN, Auteur ; Poornima MANAVALAN, Auteur ; Ashok RAGAVENDRAN, Auteur ; Alexei STORTCHEVOI, Auteur ; Clemer ABAD, Auteur ; Juan I. YOUNG, Auteur ; Patricia MACIEL, Auteur ; Michael E. TALKOWSKI, Auteur ; James F. GUSELLA, Auteur Article en page(s) : 45 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Crispr  Mbd5  Mouse  Ndd  Neurons  Transcriptomics Index. décimale : PER Périodiques Résumé : BACKGROUND: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. METHODS: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5(+/GT) mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. RESULTS: Gene expression analyses across three brain regions from Mbd5(+/GT) mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. LIMITATIONS: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. CONCLUSIONS: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes. En ligne : http://dx.doi.org/10.1186/s13229-020-00354-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons [Texte imprimé et/ou numérique] / Catarina M. SEABRA, Auteur ; Tatsiana ANEICHYK, Auteur ; Serkan ERDIN, Auteur ; Derek J. C. TAI, Auteur ; Celine E. F. DE ESCH, Auteur ; Parisa RAZAZ, Auteur ; Yu AN, Auteur ; Poornima MANAVALAN, Auteur ; Ashok RAGAVENDRAN, Auteur ; Alexei STORTCHEVOI, Auteur ; Clemer ABAD, Auteur ; Juan I. YOUNG, Auteur ; Patricia MACIEL, Auteur ; Michael E. TALKOWSKI, Auteur ; James F. GUSELLA, Auteur . - 45 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 45 p. Mots-clés : Autism spectrum disorder  Crispr  Mbd5  Mouse  Ndd  Neurons  Transcriptomics Index. décimale : PER Périodiques Résumé : BACKGROUND: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. METHODS: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5(+/GT) mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. RESULTS: Gene expression analyses across three brain regions from Mbd5(+/GT) mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. LIMITATIONS: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. CONCLUSIONS: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes. En ligne : http://dx.doi.org/10.1186/s13229-020-00354-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Neuroanatomical underpinnings of autism symptomatology in carriers and non-carriers of the 22q11.2 microdeletion / Maria GUDBRANDSEN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 46 p. Titre : Neuroanatomical underpinnings of autism symptomatology in carriers and non-carriers of the 22q11.2 microdeletion Type de document : Texte imprimé et/ou numérique Auteurs : Maria GUDBRANDSEN, Auteur ; Anke BLETSCH, Auteur ; Caroline MANN, Auteur ; Eileen DALY, Auteur ; Clodagh M. MURPHY, Auteur ; Vladimira STOENCHEVA, Auteur ; Charlotte E. BLACKMORE, Auteur ; Maria ROGDAKI, Auteur ; Leila KUSHAN, Auteur ; Carrie E. BEARDEN, Auteur ; Declan G. M. MURPHY, Auteur ; Michael C. CRAIG, Auteur ; Christine ECKER, Auteur Article en page(s) : 46 p. Langues : Anglais (eng) Mots-clés : 22q11.2 deletion syndrome  Autism spectrum disorder  Brain anatomy  Neurodevelopment  Surface-based anatomy  authors reported any financial interests or conflicts of interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: A crucial step to understanding the mechanistic underpinnings of autism spectrum disorder (ASD), is to examine if the biological underpinnings of ASD in genetic high-risk conditions, like 22q11.2 deletion syndrome (22q11.2DS), are similar to those in idiopathic illness. This study aimed to examine if ASD symptomatology in 22q11.2DS is underpinned by the same-or distinct-neural systems that mediate these symptoms in non-deletion carriers. METHODS: We examined vertex-wise estimates of cortical volume (CV), surface area (SA), and cortical thickness across 131 individuals between 6 and 25?years of age including (1) 50 individuals with 22q11.2DS, out of which n = 25 had a diagnosis of ASD, (2) 40 non-carriers of the microdeletion with a diagnosis of ASD (i.e., idiopathic ASD), and (3) 41 typically developing (TD) controls. We employed a 2-by-2 factorial design to identify neuroanatomical variability associated with the main effects of 22q11.2DS and ASD, as well as their interaction. Further, using canonical correlation analysis (CCA), we compared neuroanatomical variability associated with the complex (i.e., multivariate) clinical phenotype of ASD between 22q11.2 deletion carriers and non-carriers. RESULTS: The set of brain regions associated with the main effect of 22q11.2DS was distinct from the neuroanatomical underpinnings of the main effect of ASD. Moreover, significant 22q11.2DS-by-ASD interactions were observed for CV and SA in the dorsolateral prefrontal cortex, precentral gyrus, and posterior cingulate cortex, suggesting that the neuroanatomy of ASD is significantly modulated by 22q11.2DS (p < 0.01). We further established that the multivariate patterns of neuroanatomical variability associated with differences in symptom profiles significantly differed between 22q11.2 deletion carriers and non-carriers. LIMITATIONS: We employed a multicenter design to overcome single-site recruitment limitations; however, FreeSurfer-derived measures of surface anatomy have been shown to be highly reliable across scanner platforms and field strengths. Further, we controlled for gender to address the differing distribution between idiopathic ASD individuals and the other groups. Nonetheless, the gender distribution in our sample reflects that of the respective populations, adding to the generalizability of our results. Last, we included individuals with a relatively wide age range (i.e., 6-25?years). CONCLUSIONS: Our findings indicate that neuroanatomical correlates of ASD symptomatology in carriers of the 22q11.2 microdeletion diverge from those in idiopathic ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00356-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Neuroanatomical underpinnings of autism symptomatology in carriers and non-carriers of the 22q11.2 microdeletion [Texte imprimé et/ou numérique] / Maria GUDBRANDSEN, Auteur ; Anke BLETSCH, Auteur ; Caroline MANN, Auteur ; Eileen DALY, Auteur ; Clodagh M. MURPHY, Auteur ; Vladimira STOENCHEVA, Auteur ; Charlotte E. BLACKMORE, Auteur ; Maria ROGDAKI, Auteur ; Leila KUSHAN, Auteur ; Carrie E. BEARDEN, Auteur ; Declan G. M. MURPHY, Auteur ; Michael C. CRAIG, Auteur ; Christine ECKER, Auteur . - 46 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 46 p. Mots-clés : 22q11.2 deletion syndrome  Autism spectrum disorder  Brain anatomy  Neurodevelopment  Surface-based anatomy  authors reported any financial interests or conflicts of interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: A crucial step to understanding the mechanistic underpinnings of autism spectrum disorder (ASD), is to examine if the biological underpinnings of ASD in genetic high-risk conditions, like 22q11.2 deletion syndrome (22q11.2DS), are similar to those in idiopathic illness. This study aimed to examine if ASD symptomatology in 22q11.2DS is underpinned by the same-or distinct-neural systems that mediate these symptoms in non-deletion carriers. METHODS: We examined vertex-wise estimates of cortical volume (CV), surface area (SA), and cortical thickness across 131 individuals between 6 and 25?years of age including (1) 50 individuals with 22q11.2DS, out of which n = 25 had a diagnosis of ASD, (2) 40 non-carriers of the microdeletion with a diagnosis of ASD (i.e., idiopathic ASD), and (3) 41 typically developing (TD) controls. We employed a 2-by-2 factorial design to identify neuroanatomical variability associated with the main effects of 22q11.2DS and ASD, as well as their interaction. Further, using canonical correlation analysis (CCA), we compared neuroanatomical variability associated with the complex (i.e., multivariate) clinical phenotype of ASD between 22q11.2 deletion carriers and non-carriers. RESULTS: The set of brain regions associated with the main effect of 22q11.2DS was distinct from the neuroanatomical underpinnings of the main effect of ASD. Moreover, significant 22q11.2DS-by-ASD interactions were observed for CV and SA in the dorsolateral prefrontal cortex, precentral gyrus, and posterior cingulate cortex, suggesting that the neuroanatomy of ASD is significantly modulated by 22q11.2DS (p < 0.01). We further established that the multivariate patterns of neuroanatomical variability associated with differences in symptom profiles significantly differed between 22q11.2 deletion carriers and non-carriers. LIMITATIONS: We employed a multicenter design to overcome single-site recruitment limitations; however, FreeSurfer-derived measures of surface anatomy have been shown to be highly reliable across scanner platforms and field strengths. Further, we controlled for gender to address the differing distribution between idiopathic ASD individuals and the other groups. Nonetheless, the gender distribution in our sample reflects that of the respective populations, adding to the generalizability of our results. Last, we included individuals with a relatively wide age range (i.e., 6-25?years). CONCLUSIONS: Our findings indicate that neuroanatomical correlates of ASD symptomatology in carriers of the 22q11.2 microdeletion diverge from those in idiopathic ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00356-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Absence of parvalbumin increases mitochondria volume and branching of dendrites in inhibitory Pvalb neurons in vivo: a point of convergence of autism spectrum disorder (ASD) risk gene phenotypes / Lucia JANICKOVA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 47 p. Titre : Absence of parvalbumin increases mitochondria volume and branching of dendrites in inhibitory Pvalb neurons in vivo: a point of convergence of autism spectrum disorder (ASD) risk gene phenotypes Type de document : Texte imprimé et/ou numérique Auteurs : Lucia JANICKOVA, Auteur ; Karin Farah RECHBERGER, Auteur ; Lucas WEY, Auteur ; Beat SCHWALLER, Auteur Article en page(s) : 47 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Calcium homeostasis  Calcium-binding protein  Mitochondria  Parvalbumin  Pvalb neurons Index. décimale : PER Périodiques Résumé : BACKGROUND: In fast firing, parvalbumin (PV)-expressing (Pvalb) interneurons, PV acts as an intracellular Ca(2+) signal modulator with slow-onset kinetics. In Purkinje cells of PV(-/-) mice, adaptive/homeostatic mechanisms lead to an increase in mitochondria, organelles equally capable of delayed Ca(2+) sequestering/buffering. An inverse regulation of PV and mitochondria likewise operates in cell model systems in vitro including myotubes, epithelial cells, and oligodendrocyte-like cells overexpressing PV. Whether such opposite regulation pertains to all Pvalb neurons is currently unknown. In oligodendrocyte-like cells, PV additionally decreases growth and branching of processes in a cell-autonomous manner. METHODS: The in vivo effects of absence of PV were investigated in inhibitory Pvalb neurons expressing EGFP, present in the somatosensory and medial prefrontal cortex, striatum, thalamic reticular nucleus, hippocampal regions DG, CA3, and CA1 and cerebellum of mice either wild-type or knockout (PV(-/-)) for the Pvalb gene. Changes in Pvalb neuron morphology and PV concentrations were determined using immunofluorescence, followed by 3D-reconstruction and quantitative image analyses. RESULTS: PV deficiency led to an increase in mitochondria volume and density in the soma; the magnitude of the effect was positively correlated with the estimated PV concentrations in the various Pvalb neuron subpopulations in wild-type neurons. The increase in dendrite length and branching, as well as thickness of proximal dendrites of selected PV(-/-) Pvalb neurons is likely the result of the observed increased density and length of mitochondria in these PV(-/-) Pvalb neuron dendrites. The increased branching and soma size directly linked to the absence of PV is assumed to contribute to the increased volume of the neocortex present in juvenile PV(-/-) mice. The extended dendritic branching is in line with the hypothesis of local hyperconnectivity in autism spectrum disorder (ASD) and ASD mouse models including PV(-/-) mice, which display all ASD core symptoms and several comorbidities including cortical macrocephaly at juvenile age. CONCLUSION: PV is involved in most proposed mechanisms implicated in ASD etiology: alterations in Ca(2+) signaling affecting E/I balance, changes in mitochondria structure/function, and increased dendritic length and branching, possibly resulting in local hyperconnectivity, all in a likely cell autonomous way. En ligne : http://dx.doi.org/10.1186/s13229-020-00323-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Absence of parvalbumin increases mitochondria volume and branching of dendrites in inhibitory Pvalb neurons in vivo: a point of convergence of autism spectrum disorder (ASD) risk gene phenotypes [Texte imprimé et/ou numérique] / Lucia JANICKOVA, Auteur ; Karin Farah RECHBERGER, Auteur ; Lucas WEY, Auteur ; Beat SCHWALLER, Auteur . - 47 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 47 p. Mots-clés : Autism spectrum disorder  Calcium homeostasis  Calcium-binding protein  Mitochondria  Parvalbumin  Pvalb neurons Index. décimale : PER Périodiques Résumé : BACKGROUND: In fast firing, parvalbumin (PV)-expressing (Pvalb) interneurons, PV acts as an intracellular Ca(2+) signal modulator with slow-onset kinetics. In Purkinje cells of PV(-/-) mice, adaptive/homeostatic mechanisms lead to an increase in mitochondria, organelles equally capable of delayed Ca(2+) sequestering/buffering. An inverse regulation of PV and mitochondria likewise operates in cell model systems in vitro including myotubes, epithelial cells, and oligodendrocyte-like cells overexpressing PV. Whether such opposite regulation pertains to all Pvalb neurons is currently unknown. In oligodendrocyte-like cells, PV additionally decreases growth and branching of processes in a cell-autonomous manner. METHODS: The in vivo effects of absence of PV were investigated in inhibitory Pvalb neurons expressing EGFP, present in the somatosensory and medial prefrontal cortex, striatum, thalamic reticular nucleus, hippocampal regions DG, CA3, and CA1 and cerebellum of mice either wild-type or knockout (PV(-/-)) for the Pvalb gene. Changes in Pvalb neuron morphology and PV concentrations were determined using immunofluorescence, followed by 3D-reconstruction and quantitative image analyses. RESULTS: PV deficiency led to an increase in mitochondria volume and density in the soma; the magnitude of the effect was positively correlated with the estimated PV concentrations in the various Pvalb neuron subpopulations in wild-type neurons. The increase in dendrite length and branching, as well as thickness of proximal dendrites of selected PV(-/-) Pvalb neurons is likely the result of the observed increased density and length of mitochondria in these PV(-/-) Pvalb neuron dendrites. The increased branching and soma size directly linked to the absence of PV is assumed to contribute to the increased volume of the neocortex present in juvenile PV(-/-) mice. The extended dendritic branching is in line with the hypothesis of local hyperconnectivity in autism spectrum disorder (ASD) and ASD mouse models including PV(-/-) mice, which display all ASD core symptoms and several comorbidities including cortical macrocephaly at juvenile age. CONCLUSION: PV is involved in most proposed mechanisms implicated in ASD etiology: alterations in Ca(2+) signaling affecting E/I balance, changes in mitochondria structure/function, and increased dendritic length and branching, possibly resulting in local hyperconnectivity, all in a likely cell autonomous way. En ligne : http://dx.doi.org/10.1186/s13229-020-00323-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Defining clusters of young autistic and typically developing children based on loudness-dependent auditory electrophysiological responses / Patrick DWYER in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 48 p. Titre : Defining clusters of young autistic and typically developing children based on loudness-dependent auditory electrophysiological responses Type de document : Texte imprimé et/ou numérique Auteurs : Patrick DWYER, Auteur ; Xiaodong WANG, Auteur ; Rosanna DE MEO-MONTEIL, Auteur ; Fushing HSIEH, Auteur ; Clifford D. SARON, Auteur ; Susan M. RIVERA, Auteur Article en page(s) : 48 p. Langues : Anglais (eng) Mots-clés : Autism  Event-related potentials (ERPs)  Heterogeneity  Hierarchical clustering  Sensory processing  Subgroups  study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autistic individuals exhibit atypical patterns of sensory processing that are known to be related to quality of life, but which are also highly heterogeneous. Previous investigations of this heterogeneity have ordinarily used questionnaires and have rarely investigated sensory processing in typical development (TD) alongside autism spectrum development (ASD). METHODS: The present study used hierarchical clustering in a large sample to identify subgroups of young autistic and typically developing children based on the normalized global field power (GFP) of their event-related potentials (ERPs) to auditory stimuli of four different loudness intensities (50, 60, 70, 80?dB SPL): that is, based on an index of the relative strengths of their neural responses across these loudness conditions. RESULTS: Four clusters of participants were defined. Normalized GFP responses to sounds of different intensities differed strongly across clusters. There was considerable overlap in cluster assignments of autistic and typically developing participants, but autistic participants were more likely to display a pattern of relatively linear increases in response strength accompanied by a disproportionately strong response to 70?dB stimuli. Autistic participants displaying this pattern trended towards obtaining higher scores on assessments of cognitive abilities. There was also a trend for typically developing participants to disproportionately fall into a cluster characterized by disproportionately/nonlinearly strong 60?dB responses. Greater auditory distractibility was reported among autistic participants in a cluster characterized by disproportionately strong responses to the loudest (80?dB) sounds, and furthermore, relatively strong responses to loud sounds were correlated with auditory distractibility. This appears to provide evidence of coinciding behavioral and neural sensory atypicalities. LIMITATIONS: Replication may be needed to verify exploratory results. This analysis does not address variability related to classical ERP latencies and topographies. The sensory questionnaire employed was not specifically designed for use in autism. Hearing acuity was not measured. Variability in sensory responses unrelated to loudness is not addressed, leaving room for additional research. CONCLUSIONS: Taken together, these data demonstrate the broader benefits of using electrophysiology to explore individual differences. They illuminate different neural response patterns and suggest relationships between sensory neural responses and sensory behaviors, cognitive abilities, and autism diagnostic status. En ligne : http://dx.doi.org/10.1186/s13229-020-00352-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Defining clusters of young autistic and typically developing children based on loudness-dependent auditory electrophysiological responses [Texte imprimé et/ou numérique] / Patrick DWYER, Auteur ; Xiaodong WANG, Auteur ; Rosanna DE MEO-MONTEIL, Auteur ; Fushing HSIEH, Auteur ; Clifford D. SARON, Auteur ; Susan M. RIVERA, Auteur . - 48 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 48 p. Mots-clés : Autism  Event-related potentials (ERPs)  Heterogeneity  Hierarchical clustering  Sensory processing  Subgroups  study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autistic individuals exhibit atypical patterns of sensory processing that are known to be related to quality of life, but which are also highly heterogeneous. Previous investigations of this heterogeneity have ordinarily used questionnaires and have rarely investigated sensory processing in typical development (TD) alongside autism spectrum development (ASD). METHODS: The present study used hierarchical clustering in a large sample to identify subgroups of young autistic and typically developing children based on the normalized global field power (GFP) of their event-related potentials (ERPs) to auditory stimuli of four different loudness intensities (50, 60, 70, 80?dB SPL): that is, based on an index of the relative strengths of their neural responses across these loudness conditions. RESULTS: Four clusters of participants were defined. Normalized GFP responses to sounds of different intensities differed strongly across clusters. There was considerable overlap in cluster assignments of autistic and typically developing participants, but autistic participants were more likely to display a pattern of relatively linear increases in response strength accompanied by a disproportionately strong response to 70?dB stimuli. Autistic participants displaying this pattern trended towards obtaining higher scores on assessments of cognitive abilities. There was also a trend for typically developing participants to disproportionately fall into a cluster characterized by disproportionately/nonlinearly strong 60?dB responses. Greater auditory distractibility was reported among autistic participants in a cluster characterized by disproportionately strong responses to the loudest (80?dB) sounds, and furthermore, relatively strong responses to loud sounds were correlated with auditory distractibility. This appears to provide evidence of coinciding behavioral and neural sensory atypicalities. LIMITATIONS: Replication may be needed to verify exploratory results. This analysis does not address variability related to classical ERP latencies and topographies. The sensory questionnaire employed was not specifically designed for use in autism. Hearing acuity was not measured. Variability in sensory responses unrelated to loudness is not addressed, leaving room for additional research. CONCLUSIONS: Taken together, these data demonstrate the broader benefits of using electrophysiology to explore individual differences. They illuminate different neural response patterns and suggest relationships between sensory neural responses and sensory behaviors, cognitive abilities, and autism diagnostic status. En ligne : http://dx.doi.org/10.1186/s13229-020-00352-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Sex differences in the first impressions made by girls and boys with autism / Meredith L. COLA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 49 p. Titre : Sex differences in the first impressions made by girls and boys with autism Type de document : Texte imprimé et/ou numérique Auteurs : Meredith L. COLA, Auteur ; Samantha PLATE, Auteur ; Lisa YANKOWITZ, Auteur ; Victoria PETRULLA, Auteur ; Leila BATEMAN, Auteur ; Casey J. ZAMPELLA, Auteur ; Ashley DE MARCHENA, Auteur ; Juhi PANDEY, Auteur ; Robert T. SCHULTZ, Auteur ; Julia PARISH-MORRIS, Auteur Article en page(s) : 49 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Camouflage  First impressions  Sex differences Index. décimale : PER Périodiques Résumé : BACKGROUND: Individuals with autism spectrum disorder (ASD) are characterized by social communication challenges and repetitive behaviors that may be quickly detected by experts (Autism Res 10:653-62, 2017; American Psychiatric Association, Diagnostic and statistical manual of mental disorders, 2013). Recent research suggests that even naïve non-experts judge a variety of human dimensions using narrow windows of experience called "first impressions." Growing recognition of sex differences in a variety of observable behaviors in ASD, combined with research showing that some autistic girls and women may "camouflage" outward symptoms, suggests it may be more difficult for naïve conversation partners to detect ASD symptoms in girls. Here, we explore the first impressions made by boys and girls with ASD and typically developing (TD) peers. METHODS: Ninety-three school-aged children with ASD or TD were matched on IQ; autistic girls and boys were additionally matched on autism symptom severity using the ADOS-2. Participants completed a 5-minute "get-to-know-you" conversation with a new young adult acquaintance. Immediately after the conversation, confederates rated participants on a variety of dimensions. Our primary analysis compared conversation ratings between groups (ASD boys, ASD girls, TD boys, TD girls). RESULTS: Autistic girls were rated more positively than autistic boys by novel conversation partners (better perceived social communication ability), despite comparable autism symptom severity as rated by expert clinicians (equivalent true social communication ability). Boys with ASD were rated more negatively than typical boys and typical girls by novel conversation partners as well as expert clinicians. There was no significant difference in the first impressions made by autistic girls compared to typical girls during conversations with a novel conversation partner, but autistic girls were rated lower than typical girls by expert clinicians. LIMITATIONS: This study cannot speak to the ways in which first impressions may differ for younger children, adults, or individuals who are not verbally fluent; in addition, there were more autistic boys than girls in our sample, making it difficult to detect small effects. CONCLUSIONS: First impressions made during naturalistic conversations with non-expert conversation partners could-in combination with clinical ratings and parent report-shed light on the nature and effects of behavioral differences between girls and boys on the autism spectrum. En ligne : http://dx.doi.org/10.1186/s13229-020-00336-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Sex differences in the first impressions made by girls and boys with autism [Texte imprimé et/ou numérique] / Meredith L. COLA, Auteur ; Samantha PLATE, Auteur ; Lisa YANKOWITZ, Auteur ; Victoria PETRULLA, Auteur ; Leila BATEMAN, Auteur ; Casey J. ZAMPELLA, Auteur ; Ashley DE MARCHENA, Auteur ; Juhi PANDEY, Auteur ; Robert T. SCHULTZ, Auteur ; Julia PARISH-MORRIS, Auteur . - 49 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 49 p. Mots-clés : Autism spectrum disorder  Camouflage  First impressions  Sex differences Index. décimale : PER Périodiques Résumé : BACKGROUND: Individuals with autism spectrum disorder (ASD) are characterized by social communication challenges and repetitive behaviors that may be quickly detected by experts (Autism Res 10:653-62, 2017; American Psychiatric Association, Diagnostic and statistical manual of mental disorders, 2013). Recent research suggests that even naïve non-experts judge a variety of human dimensions using narrow windows of experience called "first impressions." Growing recognition of sex differences in a variety of observable behaviors in ASD, combined with research showing that some autistic girls and women may "camouflage" outward symptoms, suggests it may be more difficult for naïve conversation partners to detect ASD symptoms in girls. Here, we explore the first impressions made by boys and girls with ASD and typically developing (TD) peers. METHODS: Ninety-three school-aged children with ASD or TD were matched on IQ; autistic girls and boys were additionally matched on autism symptom severity using the ADOS-2. Participants completed a 5-minute "get-to-know-you" conversation with a new young adult acquaintance. Immediately after the conversation, confederates rated participants on a variety of dimensions. Our primary analysis compared conversation ratings between groups (ASD boys, ASD girls, TD boys, TD girls). RESULTS: Autistic girls were rated more positively than autistic boys by novel conversation partners (better perceived social communication ability), despite comparable autism symptom severity as rated by expert clinicians (equivalent true social communication ability). Boys with ASD were rated more negatively than typical boys and typical girls by novel conversation partners as well as expert clinicians. There was no significant difference in the first impressions made by autistic girls compared to typical girls during conversations with a novel conversation partner, but autistic girls were rated lower than typical girls by expert clinicians. LIMITATIONS: This study cannot speak to the ways in which first impressions may differ for younger children, adults, or individuals who are not verbally fluent; in addition, there were more autistic boys than girls in our sample, making it difficult to detect small effects. CONCLUSIONS: First impressions made during naturalistic conversations with non-expert conversation partners could-in combination with clinical ratings and parent report-shed light on the nature and effects of behavioral differences between girls and boys on the autism spectrum. En ligne : http://dx.doi.org/10.1186/s13229-020-00336-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

The sociability spectrum: evidence from reciprocal genetic copy number variations / Alejandro LÓPEZ-TOBÓN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 50 p. Titre : The sociability spectrum: evidence from reciprocal genetic copy number variations Type de document : Texte imprimé et/ou numérique Auteurs : Alejandro LÓPEZ-TOBÓN, Auteur ; Sebastiano TRATTARO, Auteur ; Giuseppe TESTA, Auteur Article en page(s) : 50 p. Langues : Anglais (eng) Mots-clés : 7dupASD  7q11.23  Autism spectrum disorders  Hypersociability  Sociability  William-Beuren syndrome  iPSCs Index. décimale : PER Périodiques Résumé : Sociability entails some of the most complex behaviors processed by the central nervous system. It includes the detection, integration, and interpretation of social cues and elaboration of context-specific responses that are quintessentially species-specific. There is an ever-growing accumulation of molecular associations to autism spectrum disorders (ASD), from causative genes to endophenotypes across multiple functional layers; these however, have rarely been put in context with the opposite manifestation featured in hypersociability syndromes. Genetic copy number variations (CNVs) allow to investigate the relationships between gene dosage and its corresponding phenotypes. In particular, CNVs of the 7q11.23 locus, which manifest diametrically opposite social behaviors, offer a privileged window to look into the molecular substrates underlying the developmental trajectories of the social brain. As by definition sociability is studied in humans postnatally, the developmental fluctuations causing social impairments have thus far remained a black box. Here, we review key evidence of molecular players involved at both ends of the sociability spectrum, focusing on genetic and functional associations of neuroendocrine regulators and synaptic transmission pathways. We then proceed to propose the existence of a molecular axis centered around the paradigmatic dosage imbalances at the 7q11.23 locus, regulating networks responsible for the development of social behavior in humans and highlight the key role that neurodevelopmental models from reprogrammed pluripotent cells will play for its understanding. En ligne : http://dx.doi.org/10.1186/s13229-020-00347-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] The sociability spectrum: evidence from reciprocal genetic copy number variations [Texte imprimé et/ou numérique] / Alejandro LÓPEZ-TOBÓN, Auteur ; Sebastiano TRATTARO, Auteur ; Giuseppe TESTA, Auteur . - 50 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 50 p. Mots-clés : 7dupASD  7q11.23  Autism spectrum disorders  Hypersociability  Sociability  William-Beuren syndrome  iPSCs Index. décimale : PER Périodiques Résumé : Sociability entails some of the most complex behaviors processed by the central nervous system. It includes the detection, integration, and interpretation of social cues and elaboration of context-specific responses that are quintessentially species-specific. There is an ever-growing accumulation of molecular associations to autism spectrum disorders (ASD), from causative genes to endophenotypes across multiple functional layers; these however, have rarely been put in context with the opposite manifestation featured in hypersociability syndromes. Genetic copy number variations (CNVs) allow to investigate the relationships between gene dosage and its corresponding phenotypes. In particular, CNVs of the 7q11.23 locus, which manifest diametrically opposite social behaviors, offer a privileged window to look into the molecular substrates underlying the developmental trajectories of the social brain. As by definition sociability is studied in humans postnatally, the developmental fluctuations causing social impairments have thus far remained a black box. Here, we review key evidence of molecular players involved at both ends of the sociability spectrum, focusing on genetic and functional associations of neuroendocrine regulators and synaptic transmission pathways. We then proceed to propose the existence of a molecular axis centered around the paradigmatic dosage imbalances at the 7q11.23 locus, regulating networks responsible for the development of social behavior in humans and highlight the key role that neurodevelopmental models from reprogrammed pluripotent cells will play for its understanding. En ligne : http://dx.doi.org/10.1186/s13229-020-00347-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Evidence against the "normalization" prediction of the early brain overgrowth hypothesis of autism / Lisa D. YANKOWITZ in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 51 p. Titre : Evidence against the "normalization" prediction of the early brain overgrowth hypothesis of autism Type de document : Texte imprimé et/ou numérique Auteurs : Lisa D. YANKOWITZ, Auteur ; John D. HERRINGTON, Auteur ; Benjamin E YERYS, Auteur ; Joseph A. PEREIRA, Auteur ; Juhi PANDEY, Auteur ; Robert T. SCHULTZ, Auteur Année de publication : 2020 Article en page(s) : 51 p. Langues : Anglais (eng) Mots-clés : Adolescent  Autism  Brain volume  Iq  Mri  Structural imaging Index. décimale : PER Périodiques Résumé : BACKGROUND: The frequently cited Early Overgrowth Hypothesis of autism spectrum disorder (ASD) postulates that there is overgrowth of the brain in the first 2 years of life, which is followed by a period of arrested growth leading to normalized brain volume in late childhood and beyond. While there is consistent evidence for early brain overgrowth, there is mixed evidence for normalization of brain volume by middle childhood. The outcome of this debate is important to understanding the etiology and neurodevelopmental trajectories of ASD. METHODS: Brain volume was examined in two very large single-site samples of children, adolescents, and adults. The primary sample comprised 456 6-25-year-olds (ASD n = 240, typically developing controls (TDC) n = 216), including a large number of females (n = 102) and spanning a wide IQ range (47-158). The replication sample included 175 males. High-resolution T1-weighted anatomical MRI images were examined for group differences in total brain, cerebellar, ventricular, gray, and white matter volumes. RESULTS: The ASD group had significantly larger total brain, cerebellar, gray matter, white matter, and lateral ventricular volumes in both samples, indicating that brain volume remains enlarged through young adulthood, rather than normalizing. There were no significant age or sex interactions with diagnosis in these measures. However, a significant diagnosis-by-IQ interaction was detected in the larger sample, such that increased brain volume was related to higher IQ in the TDCs, but not in the ASD group. Regions-of-significance analysis indicated that total brain volume was larger in ASD than TDC for individuals with IQ less than 115, providing a potential explanation for prior inconsistent brain size results. No relationships were found between brain volume and measures of autism symptom severity within the ASD group. LIMITATIONS: Our cross-sectional sample may not reflect individual changes over time in brain volume and cannot quantify potential changes in volume prior to age 6. CONCLUSIONS: These findings challenge the "normalization" prediction of the brain overgrowth hypothesis by demonstrating that brain enlargement persists across childhood into early adulthood. The findings raise questions about the clinical implications of brain enlargement, since we find that it neither confers cognitive benefits nor predicts increased symptom severity in ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00353-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Evidence against the "normalization" prediction of the early brain overgrowth hypothesis of autism [Texte imprimé et/ou numérique] / Lisa D. YANKOWITZ, Auteur ; John D. HERRINGTON, Auteur ; Benjamin E YERYS, Auteur ; Joseph A. PEREIRA, Auteur ; Juhi PANDEY, Auteur ; Robert T. SCHULTZ, Auteur . - 2020 . - 51 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 51 p. Mots-clés : Adolescent  Autism  Brain volume  Iq  Mri  Structural imaging Index. décimale : PER Périodiques Résumé : BACKGROUND: The frequently cited Early Overgrowth Hypothesis of autism spectrum disorder (ASD) postulates that there is overgrowth of the brain in the first 2 years of life, which is followed by a period of arrested growth leading to normalized brain volume in late childhood and beyond. While there is consistent evidence for early brain overgrowth, there is mixed evidence for normalization of brain volume by middle childhood. The outcome of this debate is important to understanding the etiology and neurodevelopmental trajectories of ASD. METHODS: Brain volume was examined in two very large single-site samples of children, adolescents, and adults. The primary sample comprised 456 6-25-year-olds (ASD n = 240, typically developing controls (TDC) n = 216), including a large number of females (n = 102) and spanning a wide IQ range (47-158). The replication sample included 175 males. High-resolution T1-weighted anatomical MRI images were examined for group differences in total brain, cerebellar, ventricular, gray, and white matter volumes. RESULTS: The ASD group had significantly larger total brain, cerebellar, gray matter, white matter, and lateral ventricular volumes in both samples, indicating that brain volume remains enlarged through young adulthood, rather than normalizing. There were no significant age or sex interactions with diagnosis in these measures. However, a significant diagnosis-by-IQ interaction was detected in the larger sample, such that increased brain volume was related to higher IQ in the TDCs, but not in the ASD group. Regions-of-significance analysis indicated that total brain volume was larger in ASD than TDC for individuals with IQ less than 115, providing a potential explanation for prior inconsistent brain size results. No relationships were found between brain volume and measures of autism symptom severity within the ASD group. LIMITATIONS: Our cross-sectional sample may not reflect individual changes over time in brain volume and cannot quantify potential changes in volume prior to age 6. CONCLUSIONS: These findings challenge the "normalization" prediction of the brain overgrowth hypothesis by demonstrating that brain enlargement persists across childhood into early adulthood. The findings raise questions about the clinical implications of brain enlargement, since we find that it neither confers cognitive benefits nor predicts increased symptom severity in ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00353-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism / Michael S. BREEN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 53 p. Titre : Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism Type de document : Texte imprimé et/ou numérique Auteurs : Michael S. BREEN, Auteur ; Andrew BROWNE, Auteur ; Gabriel E. HOFFMAN, Auteur ; Sofia STATHOPOULOS, Auteur ; Kristen BRENNAND, Auteur ; Joseph D. BUXBAUM, Auteur ; Elodie DRAPEAU, Auteur Article en page(s) : 53 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Neural progenitor cells  Neurons  RNA-sequencing  Stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability, and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions. METHODS: We developed human-induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n = 7) and their unaffected siblings (n = 6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (hiPSC-NPCs; n = 39) and induced forebrain neurons (hiPSC-neurons; n = 41). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings. RESULTS: Transcriptome analyses identified 391 differentially expressed genes (DEGs) in hiPSC-NPCs and 82 DEGs in hiPSC-neurons, when comparing cells from PMS probands and unaffected siblings (FDR En ligne : http://dx.doi.org/10.1186/s13229-020-00355-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism [Texte imprimé et/ou numérique] / Michael S. BREEN, Auteur ; Andrew BROWNE, Auteur ; Gabriel E. HOFFMAN, Auteur ; Sofia STATHOPOULOS, Auteur ; Kristen BRENNAND, Auteur ; Joseph D. BUXBAUM, Auteur ; Elodie DRAPEAU, Auteur . - 53 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 53 p. Mots-clés : Autism spectrum disorder  Neural progenitor cells  Neurons  RNA-sequencing  Stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability, and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions. METHODS: We developed human-induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n = 7) and their unaffected siblings (n = 6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (hiPSC-NPCs; n = 39) and induced forebrain neurons (hiPSC-neurons; n = 41). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings. RESULTS: Transcriptome analyses identified 391 differentially expressed genes (DEGs) in hiPSC-NPCs and 82 DEGs in hiPSC-neurons, when comparing cells from PMS probands and unaffected siblings (FDR En ligne : http://dx.doi.org/10.1186/s13229-020-00355-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns / Shreya DAS SHARMA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 52 p. Titre : Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns Type de document : Texte imprimé et/ou numérique Auteurs : Shreya DAS SHARMA, Auteur ; Rakhi PAL, Auteur ; Bharath Kumar REDDY, Auteur ; Bhuvaneish T. SELVARAJ, Auteur ; Nisha RAJ, Auteur ; Krishna Kumar SAMAGA, Auteur ; Durga J. SRINIVASAN, Auteur ; Loren ORNELAS, Auteur ; Dhruv SAREEN, Auteur ; Matthew R. LIVESEY, Auteur ; Gary J. BASSELL, Auteur ; Clive N. SVENDSEN, Auteur ; Peter C. KIND, Auteur ; Siddharthan CHANDRAN, Auteur ; Sumantra CHATTARJI, Auteur ; David J. A. WYLLIE, Auteur Article en page(s) : 52 p. Langues : Anglais (eng) Mots-clés : Action potential  Disease-modelling  Electrophysiology  Fragile X syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP). METHODS: Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced. RESULTS: Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca(2+)-activated K(+) currents and the persistent Na(+) current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na(+) channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines. CONCLUSIONS: Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered. En ligne : http://dx.doi.org/10.1186/s13229-020-00351-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns [Texte imprimé et/ou numérique] / Shreya DAS SHARMA, Auteur ; Rakhi PAL, Auteur ; Bharath Kumar REDDY, Auteur ; Bhuvaneish T. SELVARAJ, Auteur ; Nisha RAJ, Auteur ; Krishna Kumar SAMAGA, Auteur ; Durga J. SRINIVASAN, Auteur ; Loren ORNELAS, Auteur ; Dhruv SAREEN, Auteur ; Matthew R. LIVESEY, Auteur ; Gary J. BASSELL, Auteur ; Clive N. SVENDSEN, Auteur ; Peter C. KIND, Auteur ; Siddharthan CHANDRAN, Auteur ; Sumantra CHATTARJI, Auteur ; David J. A. WYLLIE, Auteur . - 52 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 52 p. Mots-clés : Action potential  Disease-modelling  Electrophysiology  Fragile X syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP). METHODS: Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced. RESULTS: Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca(2+)-activated K(+) currents and the persistent Na(+) current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na(+) channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines. CONCLUSIONS: Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered. En ligne : http://dx.doi.org/10.1186/s13229-020-00351-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Advanced paternal age as a risk factor for neurodevelopmental disorders: a translational study / Axel KRUG in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 54 p. Titre : Advanced paternal age as a risk factor for neurodevelopmental disorders: a translational study Type de document : Texte imprimé et/ou numérique Auteurs : Axel KRUG, Auteur ; Markus WÖHR, Auteur ; Dominik SEFFER, Auteur ; Henrike RIPPBERGER, Auteur ; A. Özge SUNGUR, Auteur ; Bruno DIETSCHE, Auteur ; Frederike STEIN, Auteur ; Sugirthan SIVALINGAM, Auteur ; Andreas J. FORSTNER, Auteur ; Stephanie H. WITT, Auteur ; Helene DUKAL, Auteur ; Fabian STREIT, Auteur ; Anna MAASER, Auteur ; Stefanie HEILMANN-HEIMBACH, Auteur ; Till F. M. ANDLAUER, Auteur ; Stefan HERMS, Auteur ; Per HOFFMANN, Auteur ; Marcella RIETSCHEL, Auteur ; Markus M. NÖTHEN, Auteur ; Martin LACKINGER, Auteur ; Gerhard SCHRATT, Auteur ; Michael KOCH, Auteur ; Rainer K. W. SCHWARTING, Auteur ; Tilo KIRCHER, Auteur Article en page(s) : 54 p. Langues : Anglais (eng) Mots-clés : Advanced paternal age (APA)  Diffusion tension imaging (DTI)  Social behavior  Ultrasonic vocalization  Voxel-based morphometry (VBM) Index. décimale : PER Périodiques Résumé : Advanced paternal age (APA) is a risk factor for several neurodevelopmental disorders, including autism and schizophrenia. The potential mechanisms conferring this risk are poorly understood. Here, we show that the personality traits schizotypy and neuroticism correlated with paternal age in healthy subjects (N = 677). Paternal age was further positively associated with gray matter volume (VBM, N = 342) in the right prefrontal and the right medial temporal cortex. The integrity of fiber tracts (DTI, N = 222) connecting these two areas correlated positively with paternal age. Genome-wide methylation analysis in humans showed differential methylation in APA individuals, linking APA to epigenetic mechanisms. A corresponding phenotype was obtained in our rat model. APA rats displayed social-communication deficits and emitted fewer pro-social ultrasonic vocalizations compared to controls. They further showed repetitive and stereotyped patterns of behavior, together with higher anxiety during early development. At the neurobiological level, microRNAs miR-132 and miR-134 were both differentially regulated in rats and humans depending on APA. This study demonstrates associations between APA and social behaviors across species. They might be driven by changes in the expression of microRNAs and/or epigenetic changes regulating neuronal plasticity, leading to brain morphological changes and fronto-hippocampal connectivity, a network which has been implicated in social interaction. En ligne : http://dx.doi.org/10.1186/s13229-020-00345-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Advanced paternal age as a risk factor for neurodevelopmental disorders: a translational study [Texte imprimé et/ou numérique] / Axel KRUG, Auteur ; Markus WÖHR, Auteur ; Dominik SEFFER, Auteur ; Henrike RIPPBERGER, Auteur ; A. Özge SUNGUR, Auteur ; Bruno DIETSCHE, Auteur ; Frederike STEIN, Auteur ; Sugirthan SIVALINGAM, Auteur ; Andreas J. FORSTNER, Auteur ; Stephanie H. WITT, Auteur ; Helene DUKAL, Auteur ; Fabian STREIT, Auteur ; Anna MAASER, Auteur ; Stefanie HEILMANN-HEIMBACH, Auteur ; Till F. M. ANDLAUER, Auteur ; Stefan HERMS, Auteur ; Per HOFFMANN, Auteur ; Marcella RIETSCHEL, Auteur ; Markus M. NÖTHEN, Auteur ; Martin LACKINGER, Auteur ; Gerhard SCHRATT, Auteur ; Michael KOCH, Auteur ; Rainer K. W. SCHWARTING, Auteur ; Tilo KIRCHER, Auteur . - 54 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 54 p. Mots-clés : Advanced paternal age (APA)  Diffusion tension imaging (DTI)  Social behavior  Ultrasonic vocalization  Voxel-based morphometry (VBM) Index. décimale : PER Périodiques Résumé : Advanced paternal age (APA) is a risk factor for several neurodevelopmental disorders, including autism and schizophrenia. The potential mechanisms conferring this risk are poorly understood. Here, we show that the personality traits schizotypy and neuroticism correlated with paternal age in healthy subjects (N = 677). Paternal age was further positively associated with gray matter volume (VBM, N = 342) in the right prefrontal and the right medial temporal cortex. The integrity of fiber tracts (DTI, N = 222) connecting these two areas correlated positively with paternal age. Genome-wide methylation analysis in humans showed differential methylation in APA individuals, linking APA to epigenetic mechanisms. A corresponding phenotype was obtained in our rat model. APA rats displayed social-communication deficits and emitted fewer pro-social ultrasonic vocalizations compared to controls. They further showed repetitive and stereotyped patterns of behavior, together with higher anxiety during early development. At the neurobiological level, microRNAs miR-132 and miR-134 were both differentially regulated in rats and humans depending on APA. This study demonstrates associations between APA and social behaviors across species. They might be driven by changes in the expression of microRNAs and/or epigenetic changes regulating neuronal plasticity, leading to brain morphological changes and fronto-hippocampal connectivity, a network which has been implicated in social interaction. En ligne : http://dx.doi.org/10.1186/s13229-020-00345-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism / Sara B. LINKER in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 55 p. Titre : IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism Type de document : Texte imprimé et/ou numérique Auteurs : Sara B. LINKER, Auteur ; Ana P. D. MENDES, Auteur ; Maria C. MARCHETTO, Auteur Article en page(s) : 55 p. Langues : Anglais (eng) Mots-clés : Autism  Disease modeling  Induced pluripotent stem cells (iPSC)  Insulin-like growth factor 1 (IGF-1) Index. décimale : PER Périodiques Résumé : BACKGROUND: Research evidence accumulated in the past years in both rodent and human models for autism spectrum disorders (ASD) have established insulin-like growth factor 1 (IGF-1) as one of the most promising ASD therapeutic interventions to date. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic and cellular pathophysiology of the condition; and to efficiently design drugs with widespread clinical benefits. While IGF-1 effects have been comprehensively studied in the literature, how IGF-1 activity may lead to therapeutic recovery in the ASD context is still largely unknown. METHODS: In this study, we used a previously characterized neuronal population derived from induced pluripotent stem cells (iPSC) from neurotypical controls and idiopathic ASD individuals to study the transcriptional signature of acutely and chronically IGF-1-treated cells. RESULTS: We present a comprehensive list of differentially regulated genes and molecular interactions resulting from IGF-1 exposure in developing neurons from controls and ASD individuals. Our results indicate that IGF-1 treatment has a different impact on neurons from ASD patients compared to controls. Response to IGF-1 treatment in neurons derived from ASD patients was heterogeneous and correlated with IGF-1 receptor expression, indicating that IGF-1 response may have responder and non-responder distinctions across cohorts of ASD patients. Our results suggest that caution should be used when predicting the effect of IGF-1 treatment on ASD patients using neurotypical controls. Instead, IGF-1 response should be studied in the context of ASD patients' neural cells. LIMITATIONS: The limitation of our study is that our cohort of eight sporadic ASD individuals is comorbid with macrocephaly in childhood. Future studies will address weather downstream transcriptional response of IGF-1 is comparable in non-macrocephalic ASD cohorts. CONCLUSIONS: The results presented in this study provide an important resource for researchers in the ASD field and underscore the necessity of using ASD patient lines to explore ASD neuronal-specific responses to drugs such as IGF-1. This study further helps to identify candidate pathways and targets for effective clinical intervention and may help to inform clinical trials in the future. En ligne : http://dx.doi.org/10.1186/s13229-020-00359-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism [Texte imprimé et/ou numérique] / Sara B. LINKER, Auteur ; Ana P. D. MENDES, Auteur ; Maria C. MARCHETTO, Auteur . - 55 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 55 p. Mots-clés : Autism  Disease modeling  Induced pluripotent stem cells (iPSC)  Insulin-like growth factor 1 (IGF-1) Index. décimale : PER Périodiques Résumé : BACKGROUND: Research evidence accumulated in the past years in both rodent and human models for autism spectrum disorders (ASD) have established insulin-like growth factor 1 (IGF-1) as one of the most promising ASD therapeutic interventions to date. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic and cellular pathophysiology of the condition; and to efficiently design drugs with widespread clinical benefits. While IGF-1 effects have been comprehensively studied in the literature, how IGF-1 activity may lead to therapeutic recovery in the ASD context is still largely unknown. METHODS: In this study, we used a previously characterized neuronal population derived from induced pluripotent stem cells (iPSC) from neurotypical controls and idiopathic ASD individuals to study the transcriptional signature of acutely and chronically IGF-1-treated cells. RESULTS: We present a comprehensive list of differentially regulated genes and molecular interactions resulting from IGF-1 exposure in developing neurons from controls and ASD individuals. Our results indicate that IGF-1 treatment has a different impact on neurons from ASD patients compared to controls. Response to IGF-1 treatment in neurons derived from ASD patients was heterogeneous and correlated with IGF-1 receptor expression, indicating that IGF-1 response may have responder and non-responder distinctions across cohorts of ASD patients. Our results suggest that caution should be used when predicting the effect of IGF-1 treatment on ASD patients using neurotypical controls. Instead, IGF-1 response should be studied in the context of ASD patients' neural cells. LIMITATIONS: The limitation of our study is that our cohort of eight sporadic ASD individuals is comorbid with macrocephaly in childhood. Future studies will address weather downstream transcriptional response of IGF-1 is comparable in non-macrocephalic ASD cohorts. CONCLUSIONS: The results presented in this study provide an important resource for researchers in the ASD field and underscore the necessity of using ASD patient lines to explore ASD neuronal-specific responses to drugs such as IGF-1. This study further helps to identify candidate pathways and targets for effective clinical intervention and may help to inform clinical trials in the future. En ligne : http://dx.doi.org/10.1186/s13229-020-00359-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Reduced auditory steady state responses in autism spectrum disorder / R. A. SEYMOUR in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 56 p. Titre : Reduced auditory steady state responses in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : R. A. SEYMOUR, Auteur ; G. RIPPON, Auteur ; G. GOODING-WILLIAMS, Auteur ; P. F. SOWMAN, Auteur ; K. KESSLER, Auteur Article en page(s) : 56 p. Langues : Anglais (eng) Mots-clés : Auditory steady state  Autism spectrum disorder  Gamma  Meg  Sensory Index. décimale : PER Périodiques Résumé : BACKGROUND: Auditory steady state responses (ASSRs) are elicited by clicktrains or amplitude-modulated tones, which entrain auditory cortex at their specific modulation rate. Previous research has reported reductions in ASSRs at 40?Hz for autism spectrum disorder (ASD) participants and first-degree relatives of people diagnosed with ASD (Mol Autism. 2011;2:11, Biol Psychiatry. 2007;62:192-197). METHODS: Using a 1.5?s-long auditory clicktrain stimulus, designed to elicit an ASSR at 40?Hz, this study attempted to replicate and extend these findings. Magnetencephalography (MEG) data were collected from 18 adolescent ASD participants and 18 typically developing controls. RESULTS: The ASSR localised to bilateral primary auditory regions. Regions of interest were thus defined in left and right primary auditory cortex (A1). While the transient gamma-band response (tGBR) from 0-0.1?s following presentation of the clicktrain stimulus was not different between groups, for either left or right A1, the ASD group had reduced oscillatory power at 40?Hz from 0.5 to 1.5?s post-stimulus onset, for both left and right A1. Additionally, the ASD group had reduced inter-trial coherence (phase consistency over trials) at 40?Hz from 0.64-0.82?s for right A1 and 1.04-1.22?s for left A1. LIMITATIONS: In this study, we did not conduct a clinical autism assessment (e.g. the ADOS), and therefore, it remains unclear whether ASSR power and/or ITC are associated with the clinical symptoms of ASD. CONCLUSION: Overall, our results support a specific reduction in ASSR oscillatory power and inter-trial coherence in ASD, rather than a generalised deficit in gamma-band responses. We argue that this could reflect a developmentally relevant reduction in non-linear neural processing. En ligne : http://dx.doi.org/10.1186/s13229-020-00357-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Reduced auditory steady state responses in autism spectrum disorder [Texte imprimé et/ou numérique] / R. A. SEYMOUR, Auteur ; G. RIPPON, Auteur ; G. GOODING-WILLIAMS, Auteur ; P. F. SOWMAN, Auteur ; K. KESSLER, Auteur . - 56 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 56 p. Mots-clés : Auditory steady state  Autism spectrum disorder  Gamma  Meg  Sensory Index. décimale : PER Périodiques Résumé : BACKGROUND: Auditory steady state responses (ASSRs) are elicited by clicktrains or amplitude-modulated tones, which entrain auditory cortex at their specific modulation rate. Previous research has reported reductions in ASSRs at 40?Hz for autism spectrum disorder (ASD) participants and first-degree relatives of people diagnosed with ASD (Mol Autism. 2011;2:11, Biol Psychiatry. 2007;62:192-197). METHODS: Using a 1.5?s-long auditory clicktrain stimulus, designed to elicit an ASSR at 40?Hz, this study attempted to replicate and extend these findings. Magnetencephalography (MEG) data were collected from 18 adolescent ASD participants and 18 typically developing controls. RESULTS: The ASSR localised to bilateral primary auditory regions. Regions of interest were thus defined in left and right primary auditory cortex (A1). While the transient gamma-band response (tGBR) from 0-0.1?s following presentation of the clicktrain stimulus was not different between groups, for either left or right A1, the ASD group had reduced oscillatory power at 40?Hz from 0.5 to 1.5?s post-stimulus onset, for both left and right A1. Additionally, the ASD group had reduced inter-trial coherence (phase consistency over trials) at 40?Hz from 0.64-0.82?s for right A1 and 1.04-1.22?s for left A1. LIMITATIONS: In this study, we did not conduct a clinical autism assessment (e.g. the ADOS), and therefore, it remains unclear whether ASSR power and/or ITC are associated with the clinical symptoms of ASD. CONCLUSION: Overall, our results support a specific reduction in ASSR oscillatory power and inter-trial coherence in ASD, rather than a generalised deficit in gamma-band responses. We argue that this could reflect a developmentally relevant reduction in non-linear neural processing. En ligne : http://dx.doi.org/10.1186/s13229-020-00357-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Gender identity, sexual orientation and adverse sexual experiences in autistic females / Laura A. PECORA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 57 p. Titre : Gender identity, sexual orientation and adverse sexual experiences in autistic females Type de document : Texte imprimé et/ou numérique Auteurs : Laura A. PECORA, Auteur ; Grace I. HANCOCK, Auteur ; Merrilyn HOOLEY, Auteur ; David H DEMMER, Auteur ; Tony ATTWOOD, Auteur ; Gary B. MESIBOV, Auteur ; Mark A. STOKES, Auteur Article en page(s) : 57 p. Langues : Anglais (eng) Mots-clés : Autism  Autism spectrum disorder  Female sexuality  Gender identity  Sexual orientation  Sexual vulnerabilities Index. décimale : PER Périodiques Résumé : BACKGROUND: There is growing recognition that autistic females present with more diverse gender and sexual identities than their non-autistic counterparts. Likewise, autistic females are also at an increased risk of adverse sexual experiences. As higher rates of sexual victimisation are observed in individuals with diverse sexual identities in the broader population, rates of negative sexual experiences among autistic females remain unclear. This study aimed to investigate the representation of gender and sexual diversity within autistic females and examine their rates of regretted, and unwanted, sexual encounters among females with a transgender gender identity and non-heterosexual sexual orientation. METHODS: Two hundred and ninety-five females completed the Sexual Behaviour Scale-III (SBS-III) online. Self-reported gender identity and sexual orientation were compared between 134 autistic (M(age)= 26.2?years, SD = 8.7) and 161 non-autistic females (M(age) = 22.0?years, SD = 4.6). Differences in the prevalence of negative sexual experiences were compared across diagnosis and each gender identity and sexual orientation label. RESULTS: Autistic females were more likely to identify with a transgender gender identity (p < .05) and non-heterosexual sexual orientation (p < .007) compared to non-autistic females. Autistic homosexual females were more likely to have experienced a range of negative sexual experiences than autistic heterosexual females (OR ? 3.29; p < .01) and were more likely to have experienced unwanted sexual experiences than non-autistic females regardless of sexual orientation (OR ? 2.38; p < .05). There were no differences in rates of negative sexual experiences between autistic bisexual and both autistic heterosexual and non-autistic bisexual females. Non-autistic bisexual females (OR = 0.24; p = .018) presented with a reduced risk of regretted sexual experiences than non-autistic heterosexual peers. There were no differences in negative sexual experiences across gender identity in the autistic sample. LIMITATIONS: The use of fixed format response items may have restricted participants' abilities to provide rich responses pertaining to their sexual identities and nature of negative sexual experiences. The small number of participants who identified as transgender (n = 40) limits the reliability of results pertaining to sexual experiences across gender identity. Moreover, although multiple recruitment methods were used in this study, non-representative may bias estimates of prevalence rates. Thus, the data may not be representative of the broader population. CONCLUSIONS: Results indicate that autistic females present with greater diversity in their sexual identities than individuals without autism, with those with a homosexual sexual orientation being at greater risk of experiencing adverse sexual encounters. Findings suggest the importance of increased clinical attention to this diversity and the need to provide support to facilitate the development of a healthy sexual identity and reduce the risks identified in this study. En ligne : http://dx.doi.org/10.1186/s13229-020-00363-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Gender identity, sexual orientation and adverse sexual experiences in autistic females [Texte imprimé et/ou numérique] / Laura A. PECORA, Auteur ; Grace I. HANCOCK, Auteur ; Merrilyn HOOLEY, Auteur ; David H DEMMER, Auteur ; Tony ATTWOOD, Auteur ; Gary B. MESIBOV, Auteur ; Mark A. STOKES, Auteur . - 57 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 57 p. Mots-clés : Autism  Autism spectrum disorder  Female sexuality  Gender identity  Sexual orientation  Sexual vulnerabilities Index. décimale : PER Périodiques Résumé : BACKGROUND: There is growing recognition that autistic females present with more diverse gender and sexual identities than their non-autistic counterparts. Likewise, autistic females are also at an increased risk of adverse sexual experiences. As higher rates of sexual victimisation are observed in individuals with diverse sexual identities in the broader population, rates of negative sexual experiences among autistic females remain unclear. This study aimed to investigate the representation of gender and sexual diversity within autistic females and examine their rates of regretted, and unwanted, sexual encounters among females with a transgender gender identity and non-heterosexual sexual orientation. METHODS: Two hundred and ninety-five females completed the Sexual Behaviour Scale-III (SBS-III) online. Self-reported gender identity and sexual orientation were compared between 134 autistic (M(age)= 26.2?years, SD = 8.7) and 161 non-autistic females (M(age) = 22.0?years, SD = 4.6). Differences in the prevalence of negative sexual experiences were compared across diagnosis and each gender identity and sexual orientation label. RESULTS: Autistic females were more likely to identify with a transgender gender identity (p < .05) and non-heterosexual sexual orientation (p < .007) compared to non-autistic females. Autistic homosexual females were more likely to have experienced a range of negative sexual experiences than autistic heterosexual females (OR ? 3.29; p < .01) and were more likely to have experienced unwanted sexual experiences than non-autistic females regardless of sexual orientation (OR ? 2.38; p < .05). There were no differences in rates of negative sexual experiences between autistic bisexual and both autistic heterosexual and non-autistic bisexual females. Non-autistic bisexual females (OR = 0.24; p = .018) presented with a reduced risk of regretted sexual experiences than non-autistic heterosexual peers. There were no differences in negative sexual experiences across gender identity in the autistic sample. LIMITATIONS: The use of fixed format response items may have restricted participants' abilities to provide rich responses pertaining to their sexual identities and nature of negative sexual experiences. The small number of participants who identified as transgender (n = 40) limits the reliability of results pertaining to sexual experiences across gender identity. Moreover, although multiple recruitment methods were used in this study, non-representative may bias estimates of prevalence rates. Thus, the data may not be representative of the broader population. CONCLUSIONS: Results indicate that autistic females present with greater diversity in their sexual identities than individuals without autism, with those with a homosexual sexual orientation being at greater risk of experiencing adverse sexual encounters. Findings suggest the importance of increased clinical attention to this diversity and the need to provide support to facilitate the development of a healthy sexual identity and reduce the risks identified in this study. En ligne : http://dx.doi.org/10.1186/s13229-020-00363-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Cerebral organoids as tools to identify the developmental roots of autism / Wai Kit CHAN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 58 p. Titre : Cerebral organoids as tools to identify the developmental roots of autism Type de document : Texte imprimé et/ou numérique Auteurs : Wai Kit CHAN, Auteur ; Rosie GRIFFITHS, Auteur ; David J. PRICE, Auteur ; John O. MASON, Auteur Article en page(s) : 58 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Cerebral organoids  Embryonic brain development Index. décimale : PER Périodiques Résumé : Some autism spectrum disorders (ASD) likely arise as a result of abnormalities during early embryonic development of the brain. Studying human embryonic brain development directly is challenging, mainly due to ethical and practical constraints. However, the recent development of cerebral organoids provides a powerful tool for studying both normal human embryonic brain development and, potentially, the origins of neurodevelopmental disorders including ASD. Substantial evidence now indicates that cerebral organoids can mimic normal embryonic brain development and neural cells found in organoids closely resemble their in vivo counterparts. However, with prolonged culture, significant differences begin to arise. We suggest that cerebral organoids, in their current form, are most suitable to model earlier neurodevelopmental events and processes such as neurogenesis and cortical lamination. Processes implicated in ASDs which occur at later stages of development, such as synaptogenesis and neural circuit formation, may also be modeled using organoids. The accuracy of such models will benefit from continuous improvements to protocols for organoid differentiation. En ligne : http://dx.doi.org/10.1186/s13229-020-00360-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Cerebral organoids as tools to identify the developmental roots of autism [Texte imprimé et/ou numérique] / Wai Kit CHAN, Auteur ; Rosie GRIFFITHS, Auteur ; David J. PRICE, Auteur ; John O. MASON, Auteur . - 58 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 58 p. Mots-clés : Autism spectrum disorder  Cerebral organoids  Embryonic brain development Index. décimale : PER Périodiques Résumé : Some autism spectrum disorders (ASD) likely arise as a result of abnormalities during early embryonic development of the brain. Studying human embryonic brain development directly is challenging, mainly due to ethical and practical constraints. However, the recent development of cerebral organoids provides a powerful tool for studying both normal human embryonic brain development and, potentially, the origins of neurodevelopmental disorders including ASD. Substantial evidence now indicates that cerebral organoids can mimic normal embryonic brain development and neural cells found in organoids closely resemble their in vivo counterparts. However, with prolonged culture, significant differences begin to arise. We suggest that cerebral organoids, in their current form, are most suitable to model earlier neurodevelopmental events and processes such as neurogenesis and cortical lamination. Processes implicated in ASDs which occur at later stages of development, such as synaptogenesis and neural circuit formation, may also be modeled using organoids. The accuracy of such models will benefit from continuous improvements to protocols for organoid differentiation. En ligne : http://dx.doi.org/10.1186/s13229-020-00360-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Empathic disequilibrium in two different measures of empathy predicts autism traits in neurotypical population / Ido SHALEV in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 59 p. Titre : Empathic disequilibrium in two different measures of empathy predicts autism traits in neurotypical population Type de document : Texte imprimé et/ou numérique Auteurs : Ido SHALEV, Auteur ; Florina UZEFOVSKY, Auteur Article en page(s) : 59 p. Langues : Anglais (eng) Mots-clés : Autism  Broad autism phenotype  Cognitive empathy  Emotional empathy Index. décimale : PER Périodiques Résumé : BACKGROUND: Features of autism spectrum conditions (ASC) are normally distributed within the population, giving rise to the notion of the autism spectrum. One of the hallmark features of ASC is difficulties in social communication, which relies heavily on our ability to empathize with others. Empathy comprises of both cognitive (CE) and emotional (EE) components that, together, allow us to understand another's emotions and be affected by them appropriately, while maintaining a self-other distinction. Although CE and EE depend on distinct neural and developmental trajectories, it was suggested that the two empathic capacities can influence, balance, and regulate each other. Previous findings regarding the role of emotional and cognitive empathy in ASC have been mixed. Therefore, our study aimed to investigate whether the intra-personal empathy imbalance between the cognitive and emotional components, a measure we termed empathic disequilibrium (ED), can be associated with autism traits at the neurotypical range. METHODS: Participants were 671 young-adults at the neurotypical range who self-reported their empathy, assessed using two highly validated questionnaires-the Interpersonal Reactivity Index and the Empathy Quotient, autism traits using the Autism-Spectrum Quotient, and the related traits, alexithymia, and systemizing. RESULTS: Controlling for the total empathy score, greater ED was found to be positively correlated with autism traits. Specifically, autism traits were found to be elevated in groups of individuals with relatively higher EE than CE, underscoring their imbalance. CONCLUSIONS: Our study offers a novel perspective on the understanding of the social difficulties associated with autism tendencies in the general population and has potentially important clinical implications for understanding of ASC. We also propose a novel characterization of autism tendencies based on the imbalance between EE and CE, which we term ED, as opposed to examining EE and CE separately. En ligne : http://dx.doi.org/10.1186/s13229-020-00362-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Empathic disequilibrium in two different measures of empathy predicts autism traits in neurotypical population [Texte imprimé et/ou numérique] / Ido SHALEV, Auteur ; Florina UZEFOVSKY, Auteur . - 59 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 59 p. Mots-clés : Autism  Broad autism phenotype  Cognitive empathy  Emotional empathy Index. décimale : PER Périodiques Résumé : BACKGROUND: Features of autism spectrum conditions (ASC) are normally distributed within the population, giving rise to the notion of the autism spectrum. One of the hallmark features of ASC is difficulties in social communication, which relies heavily on our ability to empathize with others. Empathy comprises of both cognitive (CE) and emotional (EE) components that, together, allow us to understand another's emotions and be affected by them appropriately, while maintaining a self-other distinction. Although CE and EE depend on distinct neural and developmental trajectories, it was suggested that the two empathic capacities can influence, balance, and regulate each other. Previous findings regarding the role of emotional and cognitive empathy in ASC have been mixed. Therefore, our study aimed to investigate whether the intra-personal empathy imbalance between the cognitive and emotional components, a measure we termed empathic disequilibrium (ED), can be associated with autism traits at the neurotypical range. METHODS: Participants were 671 young-adults at the neurotypical range who self-reported their empathy, assessed using two highly validated questionnaires-the Interpersonal Reactivity Index and the Empathy Quotient, autism traits using the Autism-Spectrum Quotient, and the related traits, alexithymia, and systemizing. RESULTS: Controlling for the total empathy score, greater ED was found to be positively correlated with autism traits. Specifically, autism traits were found to be elevated in groups of individuals with relatively higher EE than CE, underscoring their imbalance. CONCLUSIONS: Our study offers a novel perspective on the understanding of the social difficulties associated with autism tendencies in the general population and has potentially important clinical implications for understanding of ASC. We also propose a novel characterization of autism tendencies based on the imbalance between EE and CE, which we term ED, as opposed to examining EE and CE separately. En ligne : http://dx.doi.org/10.1186/s13229-020-00362-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Does decreased visual attention to faces underlie difficulties interpreting eye gaze cues in autism? / Jason W. GRIFFIN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 60 p. Titre : Does decreased visual attention to faces underlie difficulties interpreting eye gaze cues in autism? Type de document : Texte imprimé et/ou numérique Auteurs : Jason W. GRIFFIN, Auteur ; K. Suzanne SCHERF, Auteur Article en page(s) : 60 p. Langues : Anglais (eng) Mots-clés : Adolescent  Eye tracking  Face processing  Gaze following  Gaze perception  Joint attention Index. décimale : PER Périodiques Résumé : BACKGROUND: Shifts in eye gaze communicate social information that allows people to respond to another's behavior, interpret motivations driving behavior, and anticipate subsequent behavior. Understanding the social communicative nature of gaze shifts requires the ability to link eye movements and mental state information about objects in the world. Autism spectrum disorder (ASD) is characterized by atypical sensitivity to eye gaze cues, which impacts social communication and relationships. We evaluated whether reduced visual attention to faces explains this difficulty in ASD. METHODS: We employed eye-tracking technology to measure visual attention to faces and gazed-at objects in a 4-alternative forced choice paradigm in adolescents with ASD and typically developing (TD) adolescents. Participants determined the target object that an actor was looking at in ecologically rich scenes. We controlled for group differences in task engagement and data quality. RESULTS: In the Gaze Following task, adolescents with ASD were relatively impaired (Cohen's d = 0.63) in the ability to identify the target object. In contrast to predictions, both groups exhibited comparable fixation durations to faces and target objects. Among both groups, individuals who looked longer at the target objects, but not faces, performed better in the task. Finally, among the ASD group, parent SSIS-Social Skills ratings were positively associated with performance on the Gaze Following task. In the Gaze Perception task, there was a similar pattern of results, which provides internal replication of the findings that visual attention to faces is not related to difficulty interpreting eye gaze cues. Together, these findings indicate that adolescents with ASD are capable of following gaze, but have difficulty linking gaze shifts with mental state information. LIMITATIONS: Additional work is necessary to determine whether these findings generalize to individuals across the full autism spectrum. New paradigms that manipulate component processes of eye gaze processing need to be tested to confirm these interpretations. CONCLUSIONS: Reduced visual attention to faces does not appear to contribute to atypical processing of eye gaze cues among adolescents with ASD. Instead, the difficulty for individuals with ASD is related to understanding the social communicative aspects of eye gaze information, which may not be extracted from visual cues alone. En ligne : http://dx.doi.org/10.1186/s13229-020-00361-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Does decreased visual attention to faces underlie difficulties interpreting eye gaze cues in autism? [Texte imprimé et/ou numérique] / Jason W. GRIFFIN, Auteur ; K. Suzanne SCHERF, Auteur . - 60 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 60 p. Mots-clés : Adolescent  Eye tracking  Face processing  Gaze following  Gaze perception  Joint attention Index. décimale : PER Périodiques Résumé : BACKGROUND: Shifts in eye gaze communicate social information that allows people to respond to another's behavior, interpret motivations driving behavior, and anticipate subsequent behavior. Understanding the social communicative nature of gaze shifts requires the ability to link eye movements and mental state information about objects in the world. Autism spectrum disorder (ASD) is characterized by atypical sensitivity to eye gaze cues, which impacts social communication and relationships. We evaluated whether reduced visual attention to faces explains this difficulty in ASD. METHODS: We employed eye-tracking technology to measure visual attention to faces and gazed-at objects in a 4-alternative forced choice paradigm in adolescents with ASD and typically developing (TD) adolescents. Participants determined the target object that an actor was looking at in ecologically rich scenes. We controlled for group differences in task engagement and data quality. RESULTS: In the Gaze Following task, adolescents with ASD were relatively impaired (Cohen's d = 0.63) in the ability to identify the target object. In contrast to predictions, both groups exhibited comparable fixation durations to faces and target objects. Among both groups, individuals who looked longer at the target objects, but not faces, performed better in the task. Finally, among the ASD group, parent SSIS-Social Skills ratings were positively associated with performance on the Gaze Following task. In the Gaze Perception task, there was a similar pattern of results, which provides internal replication of the findings that visual attention to faces is not related to difficulty interpreting eye gaze cues. Together, these findings indicate that adolescents with ASD are capable of following gaze, but have difficulty linking gaze shifts with mental state information. LIMITATIONS: Additional work is necessary to determine whether these findings generalize to individuals across the full autism spectrum. New paradigms that manipulate component processes of eye gaze processing need to be tested to confirm these interpretations. CONCLUSIONS: Reduced visual attention to faces does not appear to contribute to atypical processing of eye gaze cues among adolescents with ASD. Instead, the difficulty for individuals with ASD is related to understanding the social communicative aspects of eye gaze information, which may not be extracted from visual cues alone. En ligne : http://dx.doi.org/10.1186/s13229-020-00361-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Coping, fostering resilience, and driving care innovation for autistic people and their families during the COVID-19 pandemic and beyond / Stephanie H. AMEIS in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 61 p. Titre : Coping, fostering resilience, and driving care innovation for autistic people and their families during the COVID-19 pandemic and beyond Type de document : Texte imprimé et/ou numérique Auteurs : Stephanie H. AMEIS, Auteur ; Meng-Chuan LAI, Auteur ; Benoit H. MULSANT, Auteur ; Peter SZATMARI, Auteur Article en page(s) : 61 p. Langues : Anglais (eng) Mots-clés : Adaptation, Psychological  Autistic Disorder/psychology  Coronavirus Infections/therapy  Health Services Accessibility  Humans  Online Social Networking  Pandemics  Pneumonia, Viral/therapy  Resilience, Psychological  Socioeconomic Factors  Telemedicine/statistics & numerical data  Vulnerable Populations/psychology  Autism  covid-19  Equity  Health services  Pandemic  Resilience  SARS-CoV-2 virus  Telehealth Index. décimale : PER Périodiques Résumé : The new coronavirus disease (COVID-19) pandemic is changing how society operates. Environmental changes, disrupted routines, and reduced access to services and social networks will have a unique impact on autistic individuals and their families and will contribute to significant deterioration in some. Access to support is crucial to address vulnerability factors, guide adjustments in home environments, and apply mitigation strategies to improve coping. The current crisis highlights that our regular care systems are not sufficient to meet the needs of the autism communities. In many parts of the world, people have shifted to online school and increased use of remote delivery of healthcare and autism supports. Access to these services needs to be increased to mitigate the negative impact of COVID-19 and future epidemics/pandemics. The rapid expansion in the use of telehealth platforms can have a positive impact on both care and research. It can help to address key priorities for the autism communities including long waitlists for assessment and care, access to services in remote locations, and restricted hours of service. However, system-level changes are urgently needed to ensure equitable access and flexible care models, especially for families and individuals who are socioeconomically disadvantaged. COVID-19 mandates the use of technology to support a broader range of care options and better meet the diverse needs of autistic people and their families. It behooves us to use this crisis as an opportunity to foster resilience not only for a given individual or their family, but also the system: to drive enduring and autism-friendly changes in healthcare, social systems, and the broader socio-ecological contexts. En ligne : http://dx.doi.org/10.1186/s13229-020-00365-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Coping, fostering resilience, and driving care innovation for autistic people and their families during the COVID-19 pandemic and beyond [Texte imprimé et/ou numérique] / Stephanie H. AMEIS, Auteur ; Meng-Chuan LAI, Auteur ; Benoit H. MULSANT, Auteur ; Peter SZATMARI, Auteur . - 61 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 61 p. Mots-clés : Adaptation, Psychological  Autistic Disorder/psychology  Coronavirus Infections/therapy  Health Services Accessibility  Humans  Online Social Networking  Pandemics  Pneumonia, Viral/therapy  Resilience, Psychological  Socioeconomic Factors  Telemedicine/statistics & numerical data  Vulnerable Populations/psychology  Autism  covid-19  Equity  Health services  Pandemic  Resilience  SARS-CoV-2 virus  Telehealth Index. décimale : PER Périodiques Résumé : The new coronavirus disease (COVID-19) pandemic is changing how society operates. Environmental changes, disrupted routines, and reduced access to services and social networks will have a unique impact on autistic individuals and their families and will contribute to significant deterioration in some. Access to support is crucial to address vulnerability factors, guide adjustments in home environments, and apply mitigation strategies to improve coping. The current crisis highlights that our regular care systems are not sufficient to meet the needs of the autism communities. In many parts of the world, people have shifted to online school and increased use of remote delivery of healthcare and autism supports. Access to these services needs to be increased to mitigate the negative impact of COVID-19 and future epidemics/pandemics. The rapid expansion in the use of telehealth platforms can have a positive impact on both care and research. It can help to address key priorities for the autism communities including long waitlists for assessment and care, access to services in remote locations, and restricted hours of service. However, system-level changes are urgently needed to ensure equitable access and flexible care models, especially for families and individuals who are socioeconomically disadvantaged. COVID-19 mandates the use of technology to support a broader range of care options and better meet the diverse needs of autistic people and their families. It behooves us to use this crisis as an opportunity to foster resilience not only for a given individual or their family, but also the system: to drive enduring and autism-friendly changes in healthcare, social systems, and the broader socio-ecological contexts. En ligne : http://dx.doi.org/10.1186/s13229-020-00365-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Targeting PPAR? in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences / Simona SCHEGGI in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 62 p. Titre : Targeting PPAR? in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences Type de document : Texte imprimé et/ou numérique Auteurs : Simona SCHEGGI, Auteur ; Francesca GUZZI, Auteur ; Giulia BRACCAGNI, Auteur ; Maria Graziella DE MONTIS, Auteur ; Marco PARENTI, Auteur ; Carla GAMBARANA, Auteur Article en page(s) : 62 p. Langues : Anglais (eng) Mots-clés : Animal models  Autism spectrum disorder  Dopamine  Reward  Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: The social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor ? (PPAR?) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments. METHODS: Male and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48-53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D(1) receptor activation, levels of expression of PPAR?, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions. RESULTS: FBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D(1) receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment. LIMITATIONS: This study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue. CONCLUSIONS: The results support the involvement of impaired motivational mechanisms in ASD-like social deficits and suggest the rationale for a possible pharmacological treatment. Moreover, the study highlights sex-related differences in the expression of ASD-like symptoms and their differential responses to FBR treatment. En ligne : http://dx.doi.org/10.1186/s13229-020-00358-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Targeting PPAR? in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences [Texte imprimé et/ou numérique] / Simona SCHEGGI, Auteur ; Francesca GUZZI, Auteur ; Giulia BRACCAGNI, Auteur ; Maria Graziella DE MONTIS, Auteur ; Marco PARENTI, Auteur ; Carla GAMBARANA, Auteur . - 62 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 62 p. Mots-clés : Animal models  Autism spectrum disorder  Dopamine  Reward  Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: The social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor ? (PPAR?) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments. METHODS: Male and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48-53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D(1) receptor activation, levels of expression of PPAR?, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions. RESULTS: FBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D(1) receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment. LIMITATIONS: This study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue. CONCLUSIONS: The results support the involvement of impaired motivational mechanisms in ASD-like social deficits and suggest the rationale for a possible pharmacological treatment. Moreover, the study highlights sex-related differences in the expression of ASD-like symptoms and their differential responses to FBR treatment. En ligne : http://dx.doi.org/10.1186/s13229-020-00358-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Alexithymia may explain the relationship between autistic traits and eating disorder psychopathology / L. VUILLIER in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 63 p. Titre : Alexithymia may explain the relationship between autistic traits and eating disorder psychopathology Type de document : Texte imprimé et/ou numérique Auteurs : L. VUILLIER, Auteur ; Z. CARTER, Auteur ; A. R. TEIXEIRA, Auteur ; R. L. MOSELEY, Auteur Article en page(s) : 63 p. Langues : Anglais (eng) Mots-clés : Alexithymia  Anorexia nervosa  Autism  Autistic traits  Eating disorders Index. décimale : PER Périodiques Résumé : BACKGROUND: Autistic people are disproportionately vulnerable to anorexia nervosa and other eating disorders (ED), and within the general population, autistic traits correlate with ED psychopathology. A putative mechanism which may underpin this heightened risk is alexithymia, a difficulty identifying and describing emotional states which is observed in both autism and ED. In two experiments with independent non-clinical samples, we explored whether alexithymia might mediate the heightened risk of eating psychopathology in individuals high in autistic traits. METHODS: Our first experiment used the PROCESS macro for SPSS to examine relationships between alexithymia (measured by the Toronto Alexithymia Scale (TAS-20)), autistic traits (autism quotient (AQ)), and eating psychopathology (Eating Attitudes Test (EAT-26)) in 121 participants. Our second experiment (n = 300) replicated and furthered this analysis by examining moderating effects of sex and controlling for anxiety and depression as covariates. We also included an additional performance-based measure of alexithymia, the Levels of Emotional Awareness Scale (LEAS). RESULTS: Study 1 suggested that TAS-20 scores mediated the relationship between heightened autistic traits and eating psychopathology. Replication and further scrutiny of this finding, in study 2, revealed that this mediation effect was partial and specific to the female participants in this sample. The mediation effect appeared to be carried by the difficulty identifying feelings subscale of the TAS-20, even when depression and anxiety were controlled for. LEAS scores, however, were not significantly related to autistic traits or eating psychopathology. LIMITATIONS: Cross-sectional data prevents any conclusions around the direction and causality of relationships between alexithymia, autistic traits, and eating psychopathology (alongside depression and anxiety), necessitating longitudinal research. Our non-clinical sample was predominantly Caucasian undergraduate students, so it remains to be seen if these results would extrapolate to clinical and/or autistic samples. Divergence between the TAS-20 and LEAS raises crucial questions regarding the construct validity of these measures. CONCLUSIONS: Our findings with respect to autistic traits suggest that alexithymia could partially explain the prevalence of ED in autistic people and may as such be an important consideration in the pathogenesis and treatment of ED in autistic and non-autistic people alike. Further research with clinical samples is critical to explore these ideas. Differences between men and women, furthermore, emphasize the importance of looking for sex-specific as well as generic risk factors in autistic and non-autistic men and women. En ligne : http://dx.doi.org/10.1186/s13229-020-00364-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Alexithymia may explain the relationship between autistic traits and eating disorder psychopathology [Texte imprimé et/ou numérique] / L. VUILLIER, Auteur ; Z. CARTER, Auteur ; A. R. TEIXEIRA, Auteur ; R. L. MOSELEY, Auteur . - 63 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 63 p. Mots-clés : Alexithymia  Anorexia nervosa  Autism  Autistic traits  Eating disorders Index. décimale : PER Périodiques Résumé : BACKGROUND: Autistic people are disproportionately vulnerable to anorexia nervosa and other eating disorders (ED), and within the general population, autistic traits correlate with ED psychopathology. A putative mechanism which may underpin this heightened risk is alexithymia, a difficulty identifying and describing emotional states which is observed in both autism and ED. In two experiments with independent non-clinical samples, we explored whether alexithymia might mediate the heightened risk of eating psychopathology in individuals high in autistic traits. METHODS: Our first experiment used the PROCESS macro for SPSS to examine relationships between alexithymia (measured by the Toronto Alexithymia Scale (TAS-20)), autistic traits (autism quotient (AQ)), and eating psychopathology (Eating Attitudes Test (EAT-26)) in 121 participants. Our second experiment (n = 300) replicated and furthered this analysis by examining moderating effects of sex and controlling for anxiety and depression as covariates. We also included an additional performance-based measure of alexithymia, the Levels of Emotional Awareness Scale (LEAS). RESULTS: Study 1 suggested that TAS-20 scores mediated the relationship between heightened autistic traits and eating psychopathology. Replication and further scrutiny of this finding, in study 2, revealed that this mediation effect was partial and specific to the female participants in this sample. The mediation effect appeared to be carried by the difficulty identifying feelings subscale of the TAS-20, even when depression and anxiety were controlled for. LEAS scores, however, were not significantly related to autistic traits or eating psychopathology. LIMITATIONS: Cross-sectional data prevents any conclusions around the direction and causality of relationships between alexithymia, autistic traits, and eating psychopathology (alongside depression and anxiety), necessitating longitudinal research. Our non-clinical sample was predominantly Caucasian undergraduate students, so it remains to be seen if these results would extrapolate to clinical and/or autistic samples. Divergence between the TAS-20 and LEAS raises crucial questions regarding the construct validity of these measures. CONCLUSIONS: Our findings with respect to autistic traits suggest that alexithymia could partially explain the prevalence of ED in autistic people and may as such be an important consideration in the pathogenesis and treatment of ED in autistic and non-autistic people alike. Further research with clinical samples is critical to explore these ideas. Differences between men and women, furthermore, emphasize the importance of looking for sex-specific as well as generic risk factors in autistic and non-autistic men and women. En ligne : http://dx.doi.org/10.1186/s13229-020-00364-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Development of the Signposting Questionnaire for Autism (SQ-A): measurement comparison with the 10-item Autism Spectrum Quotient-Child and the Strengths and Difficulties Questionnaire in the UK and Latvia / Catherine R. G. JONES in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 64 p. Titre : Development of the Signposting Questionnaire for Autism (SQ-A): measurement comparison with the 10-item Autism Spectrum Quotient-Child and the Strengths and Difficulties Questionnaire in the UK and Latvia Type de document : Texte imprimé et/ou numérique Auteurs : Catherine R. G. JONES, Auteur ; Sarah L. BARRETT, Auteur ; Ieva BITE, Auteur ; Maria LEGZDINA, Auteur ; Kristina ARINA, Auteur ; Andrea HIGGINS, Auteur ; Kyla HONEY, Auteur ; Sarah J. CARRINGTON, Auteur ; Dale F. HAY, Auteur ; Johanna CONDON, Auteur ; Susan R LEEKAM, Auteur Article en page(s) : 64 p. Langues : Anglais (eng) Mots-clés : Autism  Autism Spectrum Quotient  Diagnosis  Diagnostic Interview for Social Communication Disorders  Parent report  Signposting  Signposting Questionnaire for Autism  Strengths and Difficulties Questionnaire Index. décimale : PER Périodiques Résumé : BACKGROUND: Recognising the signs of autism spectrum disorder (ASD) can be a challenge for frontline professionals. The use of brief parent-completed questionnaires for recording the signs of ASD in school-aged children may be an important and efficient contributor to professional insight. However, to date, such questionnaires have not been designed to be used in coordination with current standardised Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic tools. Furthermore, the measurement characteristics of such questionnaires have been unexplored across countries that differ in levels of national autism service provision and cultural interpretation of the signs of ASD. METHODS: A new 14-item questionnaire (Signposting Questionnaire for Autism (SQ-A)) was developed using published DSM-5 items from a clinical interview, the Diagnostic Interview for Social Communication Disorders (DISCO). Measurement comparison was tested with the Short Autism Spectrum Quotient-Child (AQ-10) and the Strengths and Difficulties Questionnaire (SDQ). Parents of 4-11-year-old children in the UK (N = 200) and Latvia (N = 104) completed all three questionnaires. Information on clinical diagnosis provided by parents led to classification into three groups: ASD diagnosis, other conditions and no conditions. In the UK, a subsample of teachers also provided cross-informant reliability. RESULTS: In both countries, there was evidence of acceptable to good internal consistency for the SQ-A, with significantly higher scores for the ASD group and evidence of convergent and discriminant validity. There was also good parent-teacher reliability for the three measures. Notably, the questionnaires designed specifically to measure autism (SQ-A, AQ-10) performed more similarly to one another compared to the broader SDQ, with differences found for the ASD group. The overall pattern of responding to the three questionnaires was highly similar between countries. CONCLUSIONS: These results indicate the potential of the 14-item SQ-A to guide frontline professionals in the recognition of the signs of autism in children, facilitating the provision of appropriate support. En ligne : http://dx.doi.org/10.1186/s13229-020-00368-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Development of the Signposting Questionnaire for Autism (SQ-A): measurement comparison with the 10-item Autism Spectrum Quotient-Child and the Strengths and Difficulties Questionnaire in the UK and Latvia [Texte imprimé et/ou numérique] / Catherine R. G. JONES, Auteur ; Sarah L. BARRETT, Auteur ; Ieva BITE, Auteur ; Maria LEGZDINA, Auteur ; Kristina ARINA, Auteur ; Andrea HIGGINS, Auteur ; Kyla HONEY, Auteur ; Sarah J. CARRINGTON, Auteur ; Dale F. HAY, Auteur ; Johanna CONDON, Auteur ; Susan R LEEKAM, Auteur . - 64 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 64 p. Mots-clés : Autism  Autism Spectrum Quotient  Diagnosis  Diagnostic Interview for Social Communication Disorders  Parent report  Signposting  Signposting Questionnaire for Autism  Strengths and Difficulties Questionnaire Index. décimale : PER Périodiques Résumé : BACKGROUND: Recognising the signs of autism spectrum disorder (ASD) can be a challenge for frontline professionals. The use of brief parent-completed questionnaires for recording the signs of ASD in school-aged children may be an important and efficient contributor to professional insight. However, to date, such questionnaires have not been designed to be used in coordination with current standardised Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic tools. Furthermore, the measurement characteristics of such questionnaires have been unexplored across countries that differ in levels of national autism service provision and cultural interpretation of the signs of ASD. METHODS: A new 14-item questionnaire (Signposting Questionnaire for Autism (SQ-A)) was developed using published DSM-5 items from a clinical interview, the Diagnostic Interview for Social Communication Disorders (DISCO). Measurement comparison was tested with the Short Autism Spectrum Quotient-Child (AQ-10) and the Strengths and Difficulties Questionnaire (SDQ). Parents of 4-11-year-old children in the UK (N = 200) and Latvia (N = 104) completed all three questionnaires. Information on clinical diagnosis provided by parents led to classification into three groups: ASD diagnosis, other conditions and no conditions. In the UK, a subsample of teachers also provided cross-informant reliability. RESULTS: In both countries, there was evidence of acceptable to good internal consistency for the SQ-A, with significantly higher scores for the ASD group and evidence of convergent and discriminant validity. There was also good parent-teacher reliability for the three measures. Notably, the questionnaires designed specifically to measure autism (SQ-A, AQ-10) performed more similarly to one another compared to the broader SDQ, with differences found for the ASD group. The overall pattern of responding to the three questionnaires was highly similar between countries. CONCLUSIONS: These results indicate the potential of the 14-item SQ-A to guide frontline professionals in the recognition of the signs of autism in children, facilitating the provision of appropriate support. En ligne : http://dx.doi.org/10.1186/s13229-020-00368-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B / N. PERETS in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 65 p. Titre : Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B Type de document : Texte imprimé et/ou numérique Auteurs : N. PERETS, Auteur ; O. ORON, Auteur ; S. HERMAN, Auteur ; E. ELLIOTT, Auteur ; Daniel OFFEN, Auteur Article en page(s) : 65 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan-McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular vesicle that contains important molecular information of the cell and are used for cell-to-cell communication. Within the fraction of the extracellular vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. METHODS: Exosomes derived from MSC (MSC-exo) were purified, characterized, and given via intranasal administration to Shank3B KO mice (in the concentration of 10(7) particles/ml). Three weeks post treatment, the mice were tested for behavioral scoring, and their results were compared with saline-treated control and their wild-type littermates. RESULTS: Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization, and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. CONCLUSIONS: Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mouse model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model of autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation. En ligne : http://dx.doi.org/10.1186/s13229-020-00366-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B [Texte imprimé et/ou numérique] / N. PERETS, Auteur ; O. ORON, Auteur ; S. HERMAN, Auteur ; E. ELLIOTT, Auteur ; Daniel OFFEN, Auteur . - 65 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 65 p. Index. décimale : PER Périodiques Résumé : BACKGROUND: Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan-McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular vesicle that contains important molecular information of the cell and are used for cell-to-cell communication. Within the fraction of the extracellular vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. METHODS: Exosomes derived from MSC (MSC-exo) were purified, characterized, and given via intranasal administration to Shank3B KO mice (in the concentration of 10(7) particles/ml). Three weeks post treatment, the mice were tested for behavioral scoring, and their results were compared with saline-treated control and their wild-type littermates. RESULTS: Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization, and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. CONCLUSIONS: Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mouse model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model of autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation. En ligne : http://dx.doi.org/10.1186/s13229-020-00366-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis / Spyridon SIAFIS in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 66 p. Titre : Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis Type de document : Texte imprimé et/ou numérique Auteurs : Spyridon SIAFIS, Auteur ; O?ulcan ÇIRAY, Auteur ; Johannes SCHNEIDER-THOMA, Auteur ; Irene BIGHELLI, Auteur ; Marc KRAUSE, Auteur ; Alessandro RODOLICO, Auteur ; Anna CERASO, Auteur ; Giacomo DESTE, Auteur ; Maximilian HUHN, Auteur ; David FRAGUAS, Auteur ; Dimitris MAVRIDIS, Auteur ; Tony CHARMAN, Auteur ; Declan G. MURPHY, Auteur ; Mara PARELLADA, Auteur ; Celso ARANGO, Auteur ; Stefan LEUCHT, Auteur Article en page(s) : 66 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Placebo  Trials  and/or for lectures from LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS  Lohmann, Janssen, Johnson&Johnson, TEVA, MSD, Sandoz, SanofiAventis, Angelini,  Recordati, Sunovion, and Geodon Richter. David Fraguas has been a consultant and/or  has received fees from Angelini, Eisai, IE4Lab, Janssen, Lundbeck, and Otsuka. He  has also received grant support from Instituto de Salud Carlos III (Spanish Ministry  of Science, Innovation and Universities) and from Fundación Alicia Koplowitz. Mara  Parellada has received educational honoraria from Otsuka, research grants from FAK  and Fundación Mutua Madrileña (FMM), Instituto de Salud Carlos III (Spanish Ministry  of Science, Innovation and Universities) and European ERANET and H2020 calls, travel  grants from Otsuka and Janssen. Consultant for Exeltis and Servier. Celso Arango has  been a consultant to or has received honoraria or grants from Acadia, Angelini,  Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Sanofi, Servier,  Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. In the last  3 years, Maximilian Huhn has received speakers honoraria from Janssen. Declan Murphy  has received consulting fees from Roche. The other authors have nothing to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. METHODS: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . RESULTS: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = -?0.32, 95% CI [-?0.39, -?0.25], in repetitive behaviors -?0.23[-?0.32, -?0.15] and in scales measuring overall core symptoms -?0.36 [-?0.46, -?0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. LIMITATIONS: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. CONCLUSIONS: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers. En ligne : http://dx.doi.org/10.1186/s13229-020-00372-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis [Texte imprimé et/ou numérique] / Spyridon SIAFIS, Auteur ; O?ulcan ÇIRAY, Auteur ; Johannes SCHNEIDER-THOMA, Auteur ; Irene BIGHELLI, Auteur ; Marc KRAUSE, Auteur ; Alessandro RODOLICO, Auteur ; Anna CERASO, Auteur ; Giacomo DESTE, Auteur ; Maximilian HUHN, Auteur ; David FRAGUAS, Auteur ; Dimitris MAVRIDIS, Auteur ; Tony CHARMAN, Auteur ; Declan G. MURPHY, Auteur ; Mara PARELLADA, Auteur ; Celso ARANGO, Auteur ; Stefan LEUCHT, Auteur . - 66 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 66 p. Mots-clés : Autism spectrum disorder  Placebo  Trials  and/or for lectures from LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS  Lohmann, Janssen, Johnson&Johnson, TEVA, MSD, Sandoz, SanofiAventis, Angelini,  Recordati, Sunovion, and Geodon Richter. David Fraguas has been a consultant and/or  has received fees from Angelini, Eisai, IE4Lab, Janssen, Lundbeck, and Otsuka. He  has also received grant support from Instituto de Salud Carlos III (Spanish Ministry  of Science, Innovation and Universities) and from Fundación Alicia Koplowitz. Mara  Parellada has received educational honoraria from Otsuka, research grants from FAK  and Fundación Mutua Madrileña (FMM), Instituto de Salud Carlos III (Spanish Ministry  of Science, Innovation and Universities) and European ERANET and H2020 calls, travel  grants from Otsuka and Janssen. Consultant for Exeltis and Servier. Celso Arango has  been a consultant to or has received honoraria or grants from Acadia, Angelini,  Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Sanofi, Servier,  Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. In the last  3 years, Maximilian Huhn has received speakers honoraria from Janssen. Declan Murphy  has received consulting fees from Roche. The other authors have nothing to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. METHODS: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . RESULTS: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = -?0.32, 95% CI [-?0.39, -?0.25], in repetitive behaviors -?0.23[-?0.32, -?0.15] and in scales measuring overall core symptoms -?0.36 [-?0.46, -?0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. LIMITATIONS: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. CONCLUSIONS: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers. En ligne : http://dx.doi.org/10.1186/s13229-020-00372-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Dissecting the phenotypic heterogeneity in sensory features in autism spectrum disorder: a factor mixture modelling approach / J. TILLMANN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 67 p. Titre : Dissecting the phenotypic heterogeneity in sensory features in autism spectrum disorder: a factor mixture modelling approach Type de document : Texte imprimé et/ou numérique Auteurs : J. TILLMANN, Auteur ; M. ULJAREVIC, Auteur ; D. CRAWLEY, Auteur ; G. DUMAS, Auteur ; E. LOTH, Auteur ; D. MURPHY, Auteur ; Jan K. BUITELAAR, Auteur ; Tony CHARMAN, Auteur Article en page(s) : 67 p. Langues : Anglais (eng) Mots-clés : Anxiety  Autism spectrum disorder  Heterogeneity  Phenotype  Sensory features  Social-communication symptoms  of/and/or speaker for Takeda/Shire, Roche, Medice, Servier and Angelini. He is not  an employee of any of these companies, and not a stock shareholder of any of these  companies. He has no other financial or material support, including expert  testimony, patents and royalties. Julian Tillmann is a consultant to F. Hoffmann-La  Roche. Index. décimale : PER Périodiques Résumé : BACKGROUND: Heterogeneity in the phenotypic presentation of autism spectrum disorder (ASD) is apparent in the profile and the severity of sensory features. Here, we applied factor mixture modelling (FMM) to test a multidimensional factor model of sensory processing in ASD. We aimed to identify homogeneous sensory subgroups in ASD that differ intrinsically in their severity along continuous factor scores. We also investigated sensory subgroups in relation to clinical variables: sex, age, IQ, social-communication symptoms, restricted and repetitive behaviours, adaptive functioning and symptoms of anxiety and attention-deficit/hyperactivity disorder. METHODS: Three hundred thirty-two children and adults with ASD between the ages of 6 and 30?years with IQs varying between 40 and 148 were included. First, three different confirmatory factor models were fit to the 38 items of the Short Sensory Profile (SSP). Then, latent class models (with two-to-six subgroups) were evaluated. The best performing factor model, the 7-factor structure, was subsequently used in two FMMs that varied in the number of subgroups: a two-subgroup, seven-factor model and a three-subgroup and seven-factor model. RESULTS: The 'three-subgroup/seven-factor' FMM was superior to all other models based on different fit criteria. Identified subgroups differed in sensory severity from severe, moderate to low. Accounting for the potential confounding effects of age and IQ, participants in these sensory subgroups had different levels of social-communicative symptoms, restricted and repetitive behaviours, adaptive functioning skills and symptoms of inattention and anxiety. LIMITATIONS: Results were derived using a single parent-report measure of sensory features, the SSP, which limits the generalisability of findings. CONCLUSION: Sensory features can be best described by three homogeneous sensory subgroups that differ in sensory severity gradients along seven continuous factor scores. Identified sensory subgroups were further differentiated by the severity of core and co-occurring symptoms, and level of adaptive functioning, providing novel evidence on the associated clinical correlates of sensory subgroups. These sensory subgroups provide a platform to further interrogate the neurobiological and genetic correlates of altered sensory processing in ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00367-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Dissecting the phenotypic heterogeneity in sensory features in autism spectrum disorder: a factor mixture modelling approach [Texte imprimé et/ou numérique] / J. TILLMANN, Auteur ; M. ULJAREVIC, Auteur ; D. CRAWLEY, Auteur ; G. DUMAS, Auteur ; E. LOTH, Auteur ; D. MURPHY, Auteur ; Jan K. BUITELAAR, Auteur ; Tony CHARMAN, Auteur . - 67 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 67 p. Mots-clés : Anxiety  Autism spectrum disorder  Heterogeneity  Phenotype  Sensory features  Social-communication symptoms  of/and/or speaker for Takeda/Shire, Roche, Medice, Servier and Angelini. He is not  an employee of any of these companies, and not a stock shareholder of any of these  companies. He has no other financial or material support, including expert  testimony, patents and royalties. Julian Tillmann is a consultant to F. Hoffmann-La  Roche. Index. décimale : PER Périodiques Résumé : BACKGROUND: Heterogeneity in the phenotypic presentation of autism spectrum disorder (ASD) is apparent in the profile and the severity of sensory features. Here, we applied factor mixture modelling (FMM) to test a multidimensional factor model of sensory processing in ASD. We aimed to identify homogeneous sensory subgroups in ASD that differ intrinsically in their severity along continuous factor scores. We also investigated sensory subgroups in relation to clinical variables: sex, age, IQ, social-communication symptoms, restricted and repetitive behaviours, adaptive functioning and symptoms of anxiety and attention-deficit/hyperactivity disorder. METHODS: Three hundred thirty-two children and adults with ASD between the ages of 6 and 30?years with IQs varying between 40 and 148 were included. First, three different confirmatory factor models were fit to the 38 items of the Short Sensory Profile (SSP). Then, latent class models (with two-to-six subgroups) were evaluated. The best performing factor model, the 7-factor structure, was subsequently used in two FMMs that varied in the number of subgroups: a two-subgroup, seven-factor model and a three-subgroup and seven-factor model. RESULTS: The 'three-subgroup/seven-factor' FMM was superior to all other models based on different fit criteria. Identified subgroups differed in sensory severity from severe, moderate to low. Accounting for the potential confounding effects of age and IQ, participants in these sensory subgroups had different levels of social-communicative symptoms, restricted and repetitive behaviours, adaptive functioning skills and symptoms of inattention and anxiety. LIMITATIONS: Results were derived using a single parent-report measure of sensory features, the SSP, which limits the generalisability of findings. CONCLUSION: Sensory features can be best described by three homogeneous sensory subgroups that differ in sensory severity gradients along seven continuous factor scores. Identified sensory subgroups were further differentiated by the severity of core and co-occurring symptoms, and level of adaptive functioning, providing novel evidence on the associated clinical correlates of sensory subgroups. These sensory subgroups provide a platform to further interrogate the neurobiological and genetic correlates of altered sensory processing in ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00367-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms / Takafumi YUMOTO in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 68 p. Titre : Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms Type de document : Texte imprimé et/ou numérique Auteurs : Takafumi YUMOTO, Auteur ; Misaki KIMURA, Auteur ; Ryota NAGATOMO, Auteur ; Tsukika SATO, Auteur ; Shun UTSUNOMIYA, Auteur ; Natsue AOKI, Auteur ; Motoji KITAURA, Auteur ; Koji TAKAHASHI, Auteur ; Hiroshi TAKEMOTO, Auteur ; Hirotaka WATANABE, Auteur ; Hideyuki OKANO, Auteur ; Fumiaki YOSHIDA, Auteur ; Yosuke NAO, Auteur ; Taisuke TOMITA, Auteur Article en page(s) : 68 p. Langues : Anglais (eng) Mots-clés : Neuroligin 4X  Proteolysis  Synaptogenesis  Trafficking Index. décimale : PER Périodiques Résumé : BACKGROUND: Several genetic alterations, including point mutations and copy number variations in NLGN genes, have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. METHODS: In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents, and human induced pluripotent stem cell-derived neurons. RESULTS: NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. LIMITATIONS: Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on ASD model animals and patients. CONCLUSIONS: These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders. En ligne : http://dx.doi.org/10.1186/s13229-020-00373-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms [Texte imprimé et/ou numérique] / Takafumi YUMOTO, Auteur ; Misaki KIMURA, Auteur ; Ryota NAGATOMO, Auteur ; Tsukika SATO, Auteur ; Shun UTSUNOMIYA, Auteur ; Natsue AOKI, Auteur ; Motoji KITAURA, Auteur ; Koji TAKAHASHI, Auteur ; Hiroshi TAKEMOTO, Auteur ; Hirotaka WATANABE, Auteur ; Hideyuki OKANO, Auteur ; Fumiaki YOSHIDA, Auteur ; Yosuke NAO, Auteur ; Taisuke TOMITA, Auteur . - 68 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 68 p. Mots-clés : Neuroligin 4X  Proteolysis  Synaptogenesis  Trafficking Index. décimale : PER Périodiques Résumé : BACKGROUND: Several genetic alterations, including point mutations and copy number variations in NLGN genes, have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. METHODS: In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents, and human induced pluripotent stem cell-derived neurons. RESULTS: NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. LIMITATIONS: Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on ASD model animals and patients. CONCLUSIONS: These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders. En ligne : http://dx.doi.org/10.1186/s13229-020-00373-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology / Cristina CHERONI in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 69 p. Titre : Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology Type de document : Texte imprimé et/ou numérique Auteurs : Cristina CHERONI, Auteur ; Nicolò CAPORALE, Auteur ; Giuseppe TESTA, Auteur Article en page(s) : 69 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Brain organoids  Developmental neurotoxicology  Endocrine disruptors  Gene × environment  Neurodevelopmental disorders  Pluripotent stem cells Index. décimale : PER Périodiques Résumé : The complex pathophysiology of autism spectrum disorder encompasses interactions between genetic and environmental factors. On the one hand, hundreds of genes, converging at the functional level on selective biological domains such as epigenetic regulation and synaptic function, have been identified to be either causative or risk factors of autism. On the other hand, exposure to chemicals that are widespread in the environment, such as endocrine disruptors, has been associated with adverse effects on human health, including neurodevelopmental disorders. Interestingly, experimental results suggest an overlap in the regulatory pathways perturbed by genetic mutations and environmental factors, depicting convergences and complex interplays between genetic susceptibility and toxic insults. The pervasive nature of chemical exposure poses pivotal challenges for neurotoxicological studies, regulatory agencies, and policy makers. This highlights an emerging need of developing new integrative models, including biomonitoring, epidemiology, experimental, and computational tools, able to capture real-life scenarios encompassing the interaction between chronic exposure to mixture of substances and individuals' genetic backgrounds. In this review, we address the intertwined roles of genetic lesions and environmental insults. Specifically, we outline the transformative potential of stem cell models, coupled with omics analytical approaches at increasingly single cell resolution, as converging tools to experimentally dissect the pathogenic mechanisms underlying neurodevelopmental disorders, as well as to improve developmental neurotoxicology risk assessment. En ligne : http://dx.doi.org/10.1186/s13229-020-00370-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology [Texte imprimé et/ou numérique] / Cristina CHERONI, Auteur ; Nicolò CAPORALE, Auteur ; Giuseppe TESTA, Auteur . - 69 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 69 p. Mots-clés : Autism spectrum disorder  Brain organoids  Developmental neurotoxicology  Endocrine disruptors  Gene × environment  Neurodevelopmental disorders  Pluripotent stem cells Index. décimale : PER Périodiques Résumé : The complex pathophysiology of autism spectrum disorder encompasses interactions between genetic and environmental factors. On the one hand, hundreds of genes, converging at the functional level on selective biological domains such as epigenetic regulation and synaptic function, have been identified to be either causative or risk factors of autism. On the other hand, exposure to chemicals that are widespread in the environment, such as endocrine disruptors, has been associated with adverse effects on human health, including neurodevelopmental disorders. Interestingly, experimental results suggest an overlap in the regulatory pathways perturbed by genetic mutations and environmental factors, depicting convergences and complex interplays between genetic susceptibility and toxic insults. The pervasive nature of chemical exposure poses pivotal challenges for neurotoxicological studies, regulatory agencies, and policy makers. This highlights an emerging need of developing new integrative models, including biomonitoring, epidemiology, experimental, and computational tools, able to capture real-life scenarios encompassing the interaction between chronic exposure to mixture of substances and individuals' genetic backgrounds. In this review, we address the intertwined roles of genetic lesions and environmental insults. Specifically, we outline the transformative potential of stem cell models, coupled with omics analytical approaches at increasingly single cell resolution, as converging tools to experimentally dissect the pathogenic mechanisms underlying neurodevelopmental disorders, as well as to improve developmental neurotoxicology risk assessment. En ligne : http://dx.doi.org/10.1186/s13229-020-00370-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome / Monica SONZOGNI in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 70 p. Titre : Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Monica SONZOGNI, Auteur ; Peipei ZHAI, Auteur ; Edwin J. MIENTJES, Auteur ; Geeske M. VAN WOERDEN, Auteur ; Ype ELGERSMA, Auteur Article en page(s) : 70 p. Langues : Anglais (eng) Mots-clés : ASO therapy  Angelman syndrome  Behavior  Critical period  Mouse model  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. METHODS: Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. RESULTS: We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. LIMITATIONS: Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. CONCLUSIONS: Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21. En ligne : http://dx.doi.org/10.1186/s13229-020-00376-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome [Texte imprimé et/ou numérique] / Monica SONZOGNI, Auteur ; Peipei ZHAI, Auteur ; Edwin J. MIENTJES, Auteur ; Geeske M. VAN WOERDEN, Auteur ; Ype ELGERSMA, Auteur . - 70 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 70 p. Mots-clés : ASO therapy  Angelman syndrome  Behavior  Critical period  Mouse model  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. METHODS: Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. RESULTS: We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. LIMITATIONS: Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. CONCLUSIONS: Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21. En ligne : http://dx.doi.org/10.1186/s13229-020-00376-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Enhanced social learning of threat in adults with autism / Lisa ESPINOSA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 71 p. Titre : Enhanced social learning of threat in adults with autism Type de document : Texte imprimé et/ou numérique Auteurs : Lisa ESPINOSA, Auteur ; Johan LUNDIN KLEBERG, Auteur ; Björn HOFVANDER, Auteur ; Steve BERGGREN, Auteur ; Sven BÖLTE, Auteur ; Andreas OLSSON, Auteur Article en page(s) : 71 p. Langues : Anglais (eng) Mots-clés : Anxiety  Attention  Autism  Eye tracking  Skin conductance  Social cognition  Social fear learning  Vicarious threat Index. décimale : PER Périodiques Résumé : BACKGROUND: Recent theories have linked autism to challenges in prediction learning and social cognition. It is unknown, however, how autism affects learning about threats from others "demonstrators" through observation, which contains predictive learning based on social information. The aims of this study are therefore to investigate social fear learning in individual with autism spectrum disorder (ASD) and to examine whether typically developing social cognition is necessary for successful observational learning. METHODS: Adults with ASD (n = 23) and neurotypical controls (n = 25) completed a social fear learning (SFL) procedure in which participants watched a "demonstrator" receiving electrical shocks in conjunction with a previously neutral conditioned stimulus (CS+), but never with a safe control stimulus (CS-). Skin conductance was used to measure autonomic responses of learned threat responses to the CS+ versus CS-. Visual attention was measured during learning using eye tracking. To establish a non-social learning baseline, each participant also underwent a test of Pavlovian conditioning. RESULTS: During learning, individuals with ASD attended less to the demonstrator's face, and when later tested, displayed stronger observational, but not Pavlovian, autonomic indices of learning (skin conductance) compared to controls. In controls, both higher levels of attention to the demonstrator's face and trait empathy predicted diminished expressions of learning during test. LIMITATIONS: The relatively small sample size of this study and the typical IQ range of the ASD group limit the generalizability of our findings to individuals with ASD in the average intellectual ability range. CONCLUSIONS: The enhanced social threat learning in individuals with ASD may be linked to difficulties using visual attention and mental state attributions to downregulate their emotion. En ligne : http://dx.doi.org/10.1186/s13229-020-00375-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Enhanced social learning of threat in adults with autism [Texte imprimé et/ou numérique] / Lisa ESPINOSA, Auteur ; Johan LUNDIN KLEBERG, Auteur ; Björn HOFVANDER, Auteur ; Steve BERGGREN, Auteur ; Sven BÖLTE, Auteur ; Andreas OLSSON, Auteur . - 71 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 71 p. Mots-clés : Anxiety  Attention  Autism  Eye tracking  Skin conductance  Social cognition  Social fear learning  Vicarious threat Index. décimale : PER Périodiques Résumé : BACKGROUND: Recent theories have linked autism to challenges in prediction learning and social cognition. It is unknown, however, how autism affects learning about threats from others "demonstrators" through observation, which contains predictive learning based on social information. The aims of this study are therefore to investigate social fear learning in individual with autism spectrum disorder (ASD) and to examine whether typically developing social cognition is necessary for successful observational learning. METHODS: Adults with ASD (n = 23) and neurotypical controls (n = 25) completed a social fear learning (SFL) procedure in which participants watched a "demonstrator" receiving electrical shocks in conjunction with a previously neutral conditioned stimulus (CS+), but never with a safe control stimulus (CS-). Skin conductance was used to measure autonomic responses of learned threat responses to the CS+ versus CS-. Visual attention was measured during learning using eye tracking. To establish a non-social learning baseline, each participant also underwent a test of Pavlovian conditioning. RESULTS: During learning, individuals with ASD attended less to the demonstrator's face, and when later tested, displayed stronger observational, but not Pavlovian, autonomic indices of learning (skin conductance) compared to controls. In controls, both higher levels of attention to the demonstrator's face and trait empathy predicted diminished expressions of learning during test. L