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d-Cycloserine enhances durability of social skills training in autism spectrum disorder / L. K. WINK in Molecular Autism, 8 (2017)
[article]
Titre : d-Cycloserine enhances durability of social skills training in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : L. K. WINK, Auteur ; N. F. MINSHAWI, Auteur ; R. C. SHAFFER, Auteur ; M. H. PLAWECKI, Auteur ; D. J. POSEY, Auteur ; P. S. HORN, Auteur ; R. ADAMS, Auteur ; Ernest V. PEDAPATI, Auteur ; T. L. SCHAEFER, Auteur ; C. J. MCDOUGLE, Auteur ; N. B. SWIEZY, Auteur ; C. A. ERICKSON, Auteur Article en page(s) : 2p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/*drug therapy/psychology Child Child, Preschool Cycloserine/*administration & dosage/pharmacology Double-Blind Method Drug Administration Schedule Female Humans Learning/*drug effects Male Severity of Illness Index Social Behavior Treatment Outcome *Autism *Autism spectrum disorder *Social skills training *d-Cycloserine Index. décimale : PER Périodiques Résumé : BACKGROUND: d-Cycloserine (DCS) enhances extinction learning across species, but it has proven challenging to identify consistent benefit of DCS when added to therapeutic interventions. We conducted a placebo-controlled trial of DCS to potentiate social skills training in autism spectrum disorder (ASD) but found substantial improvement in both the DCS and placebo groups at the conclusion of active treatment. Here, we assess the impact of DCS 11 weeks following active treatment to evaluate the impact of DCS on treatment response durability. METHODS: Study participants included 60 outpatient youth with ASD, ages 5-11 years, all with IQ above 70, and significantly impaired social functioning who completed a 10-week active treatment phase during which they received weekly single doses of 50 mg of DCS or placebo administered 30 min prior to group social skills training. Following the 10-week active treatment phase, blinded follow-up assessments occurred at week 11 and week 22. The primary outcome measure for our durability of treatment evaluation was the parent-rated social responsiveness scale (SRS) total raw score at week 22. RESULTS: Analysis of the SRS total raw score demonstrated significant decrease for the DCS group compared to the placebo group (p = 0.042) indicating greater maintenance of treatment effect in the DCS group. DCS was well tolerated, with irritability being the most frequently reported adverse effect in both groups. CONCLUSIONS: The findings of this study suggest that DCS may help youth with ASD to maintain skills gained during sort-term social skills training. Larger-scale studies with longer follow-up will be necessary to further understand the long-term impact of DCS paired with structured social skills training. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01086475. En ligne : http://dx.doi.org/10.1186/s13229-017-0116-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331
in Molecular Autism > 8 (2017) . - 2p.[article] d-Cycloserine enhances durability of social skills training in autism spectrum disorder [Texte imprimé et/ou numérique] / L. K. WINK, Auteur ; N. F. MINSHAWI, Auteur ; R. C. SHAFFER, Auteur ; M. H. PLAWECKI, Auteur ; D. J. POSEY, Auteur ; P. S. HORN, Auteur ; R. ADAMS, Auteur ; Ernest V. PEDAPATI, Auteur ; T. L. SCHAEFER, Auteur ; C. J. MCDOUGLE, Auteur ; N. B. SWIEZY, Auteur ; C. A. ERICKSON, Auteur . - 2p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 2p.
Mots-clés : Autism Spectrum Disorder/*drug therapy/psychology Child Child, Preschool Cycloserine/*administration & dosage/pharmacology Double-Blind Method Drug Administration Schedule Female Humans Learning/*drug effects Male Severity of Illness Index Social Behavior Treatment Outcome *Autism *Autism spectrum disorder *Social skills training *d-Cycloserine Index. décimale : PER Périodiques Résumé : BACKGROUND: d-Cycloserine (DCS) enhances extinction learning across species, but it has proven challenging to identify consistent benefit of DCS when added to therapeutic interventions. We conducted a placebo-controlled trial of DCS to potentiate social skills training in autism spectrum disorder (ASD) but found substantial improvement in both the DCS and placebo groups at the conclusion of active treatment. Here, we assess the impact of DCS 11 weeks following active treatment to evaluate the impact of DCS on treatment response durability. METHODS: Study participants included 60 outpatient youth with ASD, ages 5-11 years, all with IQ above 70, and significantly impaired social functioning who completed a 10-week active treatment phase during which they received weekly single doses of 50 mg of DCS or placebo administered 30 min prior to group social skills training. Following the 10-week active treatment phase, blinded follow-up assessments occurred at week 11 and week 22. The primary outcome measure for our durability of treatment evaluation was the parent-rated social responsiveness scale (SRS) total raw score at week 22. RESULTS: Analysis of the SRS total raw score demonstrated significant decrease for the DCS group compared to the placebo group (p = 0.042) indicating greater maintenance of treatment effect in the DCS group. DCS was well tolerated, with irritability being the most frequently reported adverse effect in both groups. CONCLUSIONS: The findings of this study suggest that DCS may help youth with ASD to maintain skills gained during sort-term social skills training. Larger-scale studies with longer follow-up will be necessary to further understand the long-term impact of DCS paired with structured social skills training. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01086475. En ligne : http://dx.doi.org/10.1186/s13229-017-0116-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism / R. CHEN in Molecular Autism, 8 (2017)
[article]
Titre : Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Type de document : Texte imprimé et/ou numérique Auteurs : R. CHEN, Auteur ; L. K. DAVIS, Auteur ; S. GUTER, Auteur ; Q. WEI, Auteur ; S. JACOB, Auteur ; M. H. POTTER, Auteur ; Nancy J. COX, Auteur ; Edwin H. Jr COOK, Auteur ; J. S. SUTCLIFFE, Auteur ; B. LI, Auteur Article en page(s) : 14p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/*genetics/metabolism Endophenotypes/blood Exome Female Forkhead Transcription Factors/*genetics Genetic Predisposition to Disease Humans Jumonji Domain-Containing Histone Demethylases/*genetics Male *Mutation Nuclear Proteins/*genetics Repressor Proteins/*genetics Sequence Analysis, DNA/methods Serotonin/*blood Signal Transduction Ubiquitin-Specific Proteases/*genetics *5-ht *Autism *Autism spectrum disorder *Compound heterozygotes *De novo mutation *Endophenotype *Group-wise transmission/disequilibrium test *Hyperserotonemia *Rare variants *Serotonin *Whole exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. En ligne : http://dx.doi.org/10.1186/s13229-017-0130-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329
in Molecular Autism > 8 (2017) . - 14p.[article] Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism [Texte imprimé et/ou numérique] / R. CHEN, Auteur ; L. K. DAVIS, Auteur ; S. GUTER, Auteur ; Q. WEI, Auteur ; S. JACOB, Auteur ; M. H. POTTER, Auteur ; Nancy J. COX, Auteur ; Edwin H. Jr COOK, Auteur ; J. S. SUTCLIFFE, Auteur ; B. LI, Auteur . - 14p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 14p.
Mots-clés : Autism Spectrum Disorder/*genetics/metabolism Endophenotypes/blood Exome Female Forkhead Transcription Factors/*genetics Genetic Predisposition to Disease Humans Jumonji Domain-Containing Histone Demethylases/*genetics Male *Mutation Nuclear Proteins/*genetics Repressor Proteins/*genetics Sequence Analysis, DNA/methods Serotonin/*blood Signal Transduction Ubiquitin-Specific Proteases/*genetics *5-ht *Autism *Autism spectrum disorder *Compound heterozygotes *De novo mutation *Endophenotype *Group-wise transmission/disequilibrium test *Hyperserotonemia *Rare variants *Serotonin *Whole exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. En ligne : http://dx.doi.org/10.1186/s13229-017-0130-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 Autism spectrum disorders, endocrine disrupting compounds, and heavy metals in amniotic fluid: a case-control study / M. LONG in Molecular Autism, 10 (2019)
[article]
Titre : Autism spectrum disorders, endocrine disrupting compounds, and heavy metals in amniotic fluid: a case-control study Type de document : Texte imprimé et/ou numérique Auteurs : M. LONG, Auteur ; M. GHISARI, Auteur ; L. KJELDSEN, Auteur ; M. WIELSOE, Auteur ; B. NORGAARD-PEDERSEN, Auteur ; E. L. MORTENSEN, Auteur ; Morsi W. ABDALLAH, Auteur ; E. C. BONEFELD-JORGENSEN, Auteur Article en page(s) : 1 p. Langues : Anglais (eng) Mots-clés : Adolescent Adult Amniotic Fluid/*chemistry Animals Autism Spectrum Disorder/epidemiology/*etiology CHO Cells Case-Control Studies Child Cricetinae Cricetulus Endocrine Disruptors/*analysis/toxicity Female Humans Infant, Newborn Male Metals, Heavy/*analysis/toxicity Middle Aged *Amniotic fluid *Autism *Endocrine disrupting compounds *Receptor activity Newborn Screening Biobank and the Danish Data Protection Agency (Record No. 2009-41-3173) as well as the Central Denmark Region Ethics Committee on Health Research (Record No. M-20090066). Since all data were obtained retrospectively in an anonymized manner, there was no need to obtain consent from any of the participants.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Evidence has indicated that some non-inherited factors such as exposure to environmental pollutants are associated with neurodevelopment disorders like autism spectrum disorder (ASD). Studies report that endocrine disrupting compounds (EDCs), including polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances (PFAS), and some metals, have adverse effects on the fetal neurodevelopment. The aim of this study was to measure the amniotic fluid (AF) levels of EDCs and metals as well as the receptor transactivities induced by AF and investigate the possible link between prenatal exposure to EDCs and heavy metals and ASD risk. Methods: In this case-control study, we included AF samples of 75 ASD cases and 135 frequency-matched controls and measured the levels of the endogenous sex hormones, PFAS, and elements including heavy metals. The combined effect of endogenous hormones and EDCs on the receptor of estrogen (ER), androgen (AR), aryl hydrocarbon (AhR), and thyroid hormone-like activity were also determined and expressed as receptor ligand equivalents. We assessed the associations of AF levels of chemicals, sex hormones, and receptor activities with ASD risk using unconditional logistical regression analyses. To control for multiple comparisons, the false discovery rate (FDR) was used and q values less than 0.25 were designated as statistical significance. Results: PFAS and metals were detectable in AF samples. The ASD cases had significantly lower AF levels of PFAS than controls, and the adjusted odds ratio (OR) was 0.410 (95% CI 0.174, 0.967; p = 0.042; FDR q value = 0.437) for perfluorooctane sulfonate (PFOS). The principal component, including PFAS congeners, copper, iron, and estrogenic activity, was significantly inversely associated with ASD risk (adjusted OR = 0.100; 95% CI 0.016, 0.630; p = 0.014; FDR q value = 0.098).Testosterone level in AF weakly associated with ASD risk (adjusted OR = 1.002; 95% CI 1.000, 1.004; p = 0.05). However, after multiple comparison correction, the association was not significant (FDR q value = 0.437). No significant associations between AF-induced receptor transactivities and ASD risk were observed. The adjusted OR was 2.176 (95%CI 0.115, 41.153) for the ratio of the combined androgenic activity to combined estrogenic activity. Conclusions: The presence of PFAS and heavy metals in AF indicates that they can cross the placenta. The inverse association between levels of PFAS congeners in AF and ASD risk might relate to the weak estrogenic activities and anti-androgenic activities of PFAS.The observed tendency of positive association between the ratio of combined androgenic effect to the combined estrogenic effect and ASD risk needs further studies to explore whether EDCs together with endogenous hormones play a role in the development of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0253-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389
in Molecular Autism > 10 (2019) . - 1 p.[article] Autism spectrum disorders, endocrine disrupting compounds, and heavy metals in amniotic fluid: a case-control study [Texte imprimé et/ou numérique] / M. LONG, Auteur ; M. GHISARI, Auteur ; L. KJELDSEN, Auteur ; M. WIELSOE, Auteur ; B. NORGAARD-PEDERSEN, Auteur ; E. L. MORTENSEN, Auteur ; Morsi W. ABDALLAH, Auteur ; E. C. BONEFELD-JORGENSEN, Auteur . - 1 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 1 p.
Mots-clés : Adolescent Adult Amniotic Fluid/*chemistry Animals Autism Spectrum Disorder/epidemiology/*etiology CHO Cells Case-Control Studies Child Cricetinae Cricetulus Endocrine Disruptors/*analysis/toxicity Female Humans Infant, Newborn Male Metals, Heavy/*analysis/toxicity Middle Aged *Amniotic fluid *Autism *Endocrine disrupting compounds *Receptor activity Newborn Screening Biobank and the Danish Data Protection Agency (Record No. 2009-41-3173) as well as the Central Denmark Region Ethics Committee on Health Research (Record No. M-20090066). Since all data were obtained retrospectively in an anonymized manner, there was no need to obtain consent from any of the participants.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Evidence has indicated that some non-inherited factors such as exposure to environmental pollutants are associated with neurodevelopment disorders like autism spectrum disorder (ASD). Studies report that endocrine disrupting compounds (EDCs), including polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances (PFAS), and some metals, have adverse effects on the fetal neurodevelopment. The aim of this study was to measure the amniotic fluid (AF) levels of EDCs and metals as well as the receptor transactivities induced by AF and investigate the possible link between prenatal exposure to EDCs and heavy metals and ASD risk. Methods: In this case-control study, we included AF samples of 75 ASD cases and 135 frequency-matched controls and measured the levels of the endogenous sex hormones, PFAS, and elements including heavy metals. The combined effect of endogenous hormones and EDCs on the receptor of estrogen (ER), androgen (AR), aryl hydrocarbon (AhR), and thyroid hormone-like activity were also determined and expressed as receptor ligand equivalents. We assessed the associations of AF levels of chemicals, sex hormones, and receptor activities with ASD risk using unconditional logistical regression analyses. To control for multiple comparisons, the false discovery rate (FDR) was used and q values less than 0.25 were designated as statistical significance. Results: PFAS and metals were detectable in AF samples. The ASD cases had significantly lower AF levels of PFAS than controls, and the adjusted odds ratio (OR) was 0.410 (95% CI 0.174, 0.967; p = 0.042; FDR q value = 0.437) for perfluorooctane sulfonate (PFOS). The principal component, including PFAS congeners, copper, iron, and estrogenic activity, was significantly inversely associated with ASD risk (adjusted OR = 0.100; 95% CI 0.016, 0.630; p = 0.014; FDR q value = 0.098).Testosterone level in AF weakly associated with ASD risk (adjusted OR = 1.002; 95% CI 1.000, 1.004; p = 0.05). However, after multiple comparison correction, the association was not significant (FDR q value = 0.437). No significant associations between AF-induced receptor transactivities and ASD risk were observed. The adjusted OR was 2.176 (95%CI 0.115, 41.153) for the ratio of the combined androgenic activity to combined estrogenic activity. Conclusions: The presence of PFAS and heavy metals in AF indicates that they can cross the placenta. The inverse association between levels of PFAS congeners in AF and ASD risk might relate to the weak estrogenic activities and anti-androgenic activities of PFAS.The observed tendency of positive association between the ratio of combined androgenic effect to the combined estrogenic effect and ASD risk needs further studies to explore whether EDCs together with endogenous hormones play a role in the development of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0253-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells / P. WANG in Molecular Autism, 8 (2017)
[article]
Titre : CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells Type de document : Texte imprimé et/ou numérique Auteurs : P. WANG, Auteur ; R. MOKHTARI, Auteur ; E. PEDROSA, Auteur ; M. KIRSCHENBAUM, Auteur ; C. BAYRAK, Auteur ; D. ZHENG, Auteur ; H. M. LACHMAN, Auteur Article en page(s) : 11p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics Bipolar Disorder/genetics CRISPR-Cas Systems Cell Differentiation Cells, Cultured DNA-Binding Proteins/*genetics Gene Expression Profiling/*methods Gene Expression Regulation Gene Knockout Techniques *Gene Regulatory Networks Humans Induced Pluripotent Stem Cells/*cytology Mental Disorders/*genetics Mutation Organoids/*cytology Schizophrenia/genetics Sequence Analysis, RNA/*methods Telencephalon/*cytology Transcription Factors/*genetics *Autism *Beta-catenin *Bipolar disorder *Cancer *Dlx6-as1 *Distal-less homeobox *Gabaergic *Hmga2 *Schizophrenia *Tcf4 *Wnt *Znf132 Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8(+/-)) vs isogenic controls (CHD8(+/-)), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8(+/-) neuronal cells. METHODS: In the current study, RNA-seq was carried out on CHD8(+/-) and isogenic control (CHD8(+/+)) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. RESULTS: TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/beta-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8(+/-) DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/beta-catenin signaling in a subgroup of affected individuals. CONCLUSIONS: Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits. En ligne : http://dx.doi.org/10.1186/s13229-017-0124-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331
in Molecular Autism > 8 (2017) . - 11p.[article] CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells [Texte imprimé et/ou numérique] / P. WANG, Auteur ; R. MOKHTARI, Auteur ; E. PEDROSA, Auteur ; M. KIRSCHENBAUM, Auteur ; C. BAYRAK, Auteur ; D. ZHENG, Auteur ; H. M. LACHMAN, Auteur . - 11p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 11p.
Mots-clés : Autism Spectrum Disorder/genetics Bipolar Disorder/genetics CRISPR-Cas Systems Cell Differentiation Cells, Cultured DNA-Binding Proteins/*genetics Gene Expression Profiling/*methods Gene Expression Regulation Gene Knockout Techniques *Gene Regulatory Networks Humans Induced Pluripotent Stem Cells/*cytology Mental Disorders/*genetics Mutation Organoids/*cytology Schizophrenia/genetics Sequence Analysis, RNA/*methods Telencephalon/*cytology Transcription Factors/*genetics *Autism *Beta-catenin *Bipolar disorder *Cancer *Dlx6-as1 *Distal-less homeobox *Gabaergic *Hmga2 *Schizophrenia *Tcf4 *Wnt *Znf132 Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8(+/-)) vs isogenic controls (CHD8(+/-)), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8(+/-) neuronal cells. METHODS: In the current study, RNA-seq was carried out on CHD8(+/-) and isogenic control (CHD8(+/+)) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. RESULTS: TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/beta-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8(+/-) DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/beta-catenin signaling in a subgroup of affected individuals. CONCLUSIONS: Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits. En ligne : http://dx.doi.org/10.1186/s13229-017-0124-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 Disconnection from others in autism is more than just a feeling: whole-brain neural synchrony in adults during implicit processing of emotional faces / R. MENNELLA in Molecular Autism, 8 (2017)
[article]
Titre : Disconnection from others in autism is more than just a feeling: whole-brain neural synchrony in adults during implicit processing of emotional faces Type de document : Texte imprimé et/ou numérique Auteurs : R. MENNELLA, Auteur ; R. C. LEUNG, Auteur ; M. J. TAYLOR, Auteur ; B. T. DUNKLEY, Auteur Article en page(s) : 7p. Langues : Anglais (eng) Mots-clés : Adult Autism Spectrum Disorder/*psychology Brain/*physiology Brain Mapping/*methods Facial Expression Female Humans Image Processing, Computer-Assisted Magnetoencephalography/*methods Male Social Perception Young Adult *Autism *Emotional faces *Functional connectivity *Magnetoencephalography *Social brain *Young adults Index. décimale : PER Périodiques Résumé : BACKGROUND: Socio-emotional difficulties in autism spectrum disorder (ASD) are thought to reflect impaired functional connectivity within the "social brain". Nonetheless, a whole-brain characterization of the fast responses in functional connectivity during implicit processing of emotional faces in adults with ASD is lacking. METHODS: The present study used magnetoencephalography to investigate early responses in functional connectivity, as measured by interregional phase synchronization, during implicit processing of angry, neutral and happy faces. The sample (n = 44) consisted of 22 young adults with ASD and 22 age- and sex-matched typically developed (TD) controls. RESULTS: Reduced phase-synchrony in the beta band around 300 ms emerged during processing of angry faces in the ASD compared to TD group, involving key areas of the social brain. In the same time window, de-synchronization in the beta band in the amygdala was reduced in the ASD group across conditions. CONCLUSIONS: This is the first demonstration of atypical global and local synchrony patterns in the social brain in adults with ASD during implicit processing of emotional faces. The present results replicate and substantially extend previous findings on adolescents, highlighting that atypical brain synchrony during processing of socio-emotional stimuli is a hallmark of clinical sequelae in autism. En ligne : http://dx.doi.org/10.1186/s13229-017-0123-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 7p.[article] Disconnection from others in autism is more than just a feeling: whole-brain neural synchrony in adults during implicit processing of emotional faces [Texte imprimé et/ou numérique] / R. MENNELLA, Auteur ; R. C. LEUNG, Auteur ; M. J. TAYLOR, Auteur ; B. T. DUNKLEY, Auteur . - 7p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 7p.
Mots-clés : Adult Autism Spectrum Disorder/*psychology Brain/*physiology Brain Mapping/*methods Facial Expression Female Humans Image Processing, Computer-Assisted Magnetoencephalography/*methods Male Social Perception Young Adult *Autism *Emotional faces *Functional connectivity *Magnetoencephalography *Social brain *Young adults Index. décimale : PER Périodiques Résumé : BACKGROUND: Socio-emotional difficulties in autism spectrum disorder (ASD) are thought to reflect impaired functional connectivity within the "social brain". Nonetheless, a whole-brain characterization of the fast responses in functional connectivity during implicit processing of emotional faces in adults with ASD is lacking. METHODS: The present study used magnetoencephalography to investigate early responses in functional connectivity, as measured by interregional phase synchronization, during implicit processing of angry, neutral and happy faces. The sample (n = 44) consisted of 22 young adults with ASD and 22 age- and sex-matched typically developed (TD) controls. RESULTS: Reduced phase-synchrony in the beta band around 300 ms emerged during processing of angry faces in the ASD compared to TD group, involving key areas of the social brain. In the same time window, de-synchronization in the beta band in the amygdala was reduced in the ASD group across conditions. CONCLUSIONS: This is the first demonstration of atypical global and local synchrony patterns in the social brain in adults with ASD during implicit processing of emotional faces. The present results replicate and substantially extend previous findings on adolescents, highlighting that atypical brain synchrony during processing of socio-emotional stimuli is a hallmark of clinical sequelae in autism. En ligne : http://dx.doi.org/10.1186/s13229-017-0123-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 Neural circuitry at age 6 months associated with later repetitive behavior and sensory responsiveness in autism / J. J. WOLFF in Molecular Autism, 8 (2017)
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