30 recherche sur le mot-clé 'Autism Spectrum Disorder/genetics'

Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder / W. FYKE in Autism Research, 14-9 (September 2021)  

Public ISBD [article]  inAutism Research > 14-9 (September 2021) . - p.1854-1872 Titre : Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : W. FYKE, Auteur ; M. PREMOLI, Auteur ; V. ECHEVERRY ALZATE, Auteur ; J. A. LÓPEZ-MORENO, Auteur ; V. LEMAIRE-MAYO, Auteur ; W. E. CRUSIO, Auteur ; G. MARSICANO, Auteur ; M. WOHR, Auteur ; S. PIETROPAOLO, Auteur Article en page(s) : p.1854-1872 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Communication  Disease Models, Animal  Female  Male  Mice  Mice, Knockout  Receptor, Cannabinoid, CB1/genetics  Social Behavior  Social Interaction  cannabinoid receptor  mouse models  phenotype  sex differences  ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder [Texte imprimé et/ou numérique] / W. FYKE, Auteur ; M. PREMOLI, Auteur ; V. ECHEVERRY ALZATE, Auteur ; J. A. LÓPEZ-MORENO, Auteur ; V. LEMAIRE-MAYO, Auteur ; W. E. CRUSIO, Auteur ; G. MARSICANO, Auteur ; M. WOHR, Auteur ; S. PIETROPAOLO, Auteur . - p.1854-1872. Langues : Anglais (eng) in Autism Research > 14-9 (September 2021) . - p.1854-1872 Mots-clés : Animals  Autism Spectrum Disorder/genetics  Communication  Disease Models, Animal  Female  Male  Mice  Mice, Knockout  Receptor, Cannabinoid, CB1/genetics  Social Behavior  Social Interaction  cannabinoid receptor  mouse models  phenotype  sex differences  ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder / T. SAELIW in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 27p. Titre : Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : T. SAELIW, Auteur ; C. TANGSUWANSRI, Auteur ; S. THONGKORN, Auteur ; W. CHONCHAIYA, Auteur ; K. SUPHAPEETIPORN, Auteur ; A. MUTIRANGURA, Auteur ; T. TENCOMNAO, Auteur ; V. W. HU, Auteur ; T. SARACHANA, Auteur Article en page(s) : 27p. Langues : Anglais (eng) Mots-clés : Alu Elements  Autism Spectrum Disorder/genetics  Case-Control Studies  Cells, Cultured  DNA Methylation  Epigenesis, Genetic  Female  Gene Regulatory Networks  Genome, Human  Humans  Male  Transcriptome  Autism spectrum disorder  Epigenetic regulation  Gene expression profiles  Lymphoblastoid cell lines  Neuroinflammation  Retrotransposon  Sex bias  Subgrouping Index. décimale : PER Périodiques Résumé : Background: Alu elements are a group of repetitive elements that can influence gene expression through CpG residues and transcription factor binding. Altered gene expression and methylation profiles have been reported in various tissues and cell lines from individuals with autism spectrum disorder (ASD). However, the role of Alu elements in ASD remains unclear. We thus investigated whether Alu elements are associated with altered gene expression profiles in ASD. Methods: We obtained five blood-based gene expression profiles from the Gene Expression Omnibus database and human Alu-inserted gene lists from the TranspoGene database. Differentially expressed genes (DEGs) in ASD were identified from each study and overlapped with the human Alu-inserted genes. The biological functions and networks of Alu-inserted DEGs were then predicted by Ingenuity Pathway Analysis (IPA). A combined bisulfite restriction analysis of lymphoblastoid cell lines (LCLs) derived from 36 ASD and 20 sex- and age-matched unaffected individuals was performed to assess the global DNA methylation levels within Alu elements, and the Alu expression levels were determined by quantitative RT-PCR. Results: In ASD blood or blood-derived cells, 320 Alu-inserted genes were reproducibly differentially expressed. Biological function and pathway analysis showed that these genes were significantly associated with neurodevelopmental disorders and neurological functions involved in ASD etiology. Interestingly, estrogen receptor and androgen signaling pathways implicated in the sex bias of ASD, as well as IL-6 signaling and neuroinflammation signaling pathways, were also highlighted. Alu methylation was not significantly different between the ASD and sex- and age-matched control groups. However, significantly altered Alu methylation patterns were observed in ASD cases sub-grouped based on Autism Diagnostic Interview-Revised scores compared with matched controls. Quantitative RT-PCR analysis of Alu expression also showed significant differences between ASD subgroups. Interestingly, Alu expression was correlated with methylation status in one phenotypic ASD subgroup. Conclusion: Alu methylation and expression were altered in LCLs from ASD subgroups. Our findings highlight the association of Alu elements with gene dysregulation in ASD blood samples and warrant further investigation. Moreover, the classification of ASD individuals into subgroups based on phenotypes may be beneficial and could provide insights into the still unknown etiology and the underlying mechanisms of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0213-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder [Texte imprimé et/ou numérique] / T. SAELIW, Auteur ; C. TANGSUWANSRI, Auteur ; S. THONGKORN, Auteur ; W. CHONCHAIYA, Auteur ; K. SUPHAPEETIPORN, Auteur ; A. MUTIRANGURA, Auteur ; T. TENCOMNAO, Auteur ; V. W. HU, Auteur ; T. SARACHANA, Auteur . - 27p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 27p. Mots-clés : Alu Elements  Autism Spectrum Disorder/genetics  Case-Control Studies  Cells, Cultured  DNA Methylation  Epigenesis, Genetic  Female  Gene Regulatory Networks  Genome, Human  Humans  Male  Transcriptome  Autism spectrum disorder  Epigenetic regulation  Gene expression profiles  Lymphoblastoid cell lines  Neuroinflammation  Retrotransposon  Sex bias  Subgrouping Index. décimale : PER Périodiques Résumé : Background: Alu elements are a group of repetitive elements that can influence gene expression through CpG residues and transcription factor binding. Altered gene expression and methylation profiles have been reported in various tissues and cell lines from individuals with autism spectrum disorder (ASD). However, the role of Alu elements in ASD remains unclear. We thus investigated whether Alu elements are associated with altered gene expression profiles in ASD. Methods: We obtained five blood-based gene expression profiles from the Gene Expression Omnibus database and human Alu-inserted gene lists from the TranspoGene database. Differentially expressed genes (DEGs) in ASD were identified from each study and overlapped with the human Alu-inserted genes. The biological functions and networks of Alu-inserted DEGs were then predicted by Ingenuity Pathway Analysis (IPA). A combined bisulfite restriction analysis of lymphoblastoid cell lines (LCLs) derived from 36 ASD and 20 sex- and age-matched unaffected individuals was performed to assess the global DNA methylation levels within Alu elements, and the Alu expression levels were determined by quantitative RT-PCR. Results: In ASD blood or blood-derived cells, 320 Alu-inserted genes were reproducibly differentially expressed. Biological function and pathway analysis showed that these genes were significantly associated with neurodevelopmental disorders and neurological functions involved in ASD etiology. Interestingly, estrogen receptor and androgen signaling pathways implicated in the sex bias of ASD, as well as IL-6 signaling and neuroinflammation signaling pathways, were also highlighted. Alu methylation was not significantly different between the ASD and sex- and age-matched control groups. However, significantly altered Alu methylation patterns were observed in ASD cases sub-grouped based on Autism Diagnostic Interview-Revised scores compared with matched controls. Quantitative RT-PCR analysis of Alu expression also showed significant differences between ASD subgroups. Interestingly, Alu expression was correlated with methylation status in one phenotypic ASD subgroup. Conclusion: Alu methylation and expression were altered in LCLs from ASD subgroups. Our findings highlight the association of Alu elements with gene dysregulation in ASD blood samples and warrant further investigation. Moreover, the classification of ASD individuals into subgroups based on phenotypes may be beneficial and could provide insights into the still unknown etiology and the underlying mechanisms of ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0213-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder / J. PIJUAN in Autism Research, 14-6 (June 2021)  

Public ISBD [article]  inAutism Research > 14-6 (June 2021) . - p.1088-1100 Titre : PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur Article en page(s) : p.1088-1100 Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics  Autism Spectrum Disorder/genetics  DNA Copy Number Variations  Exome  Genetic Predisposition to Disease/genetics  Humans  Nerve Tissue Proteins/genetics  Receptors, Cell Surface  Lrrc40  Plxna2  autism spectrum disorder  diagnosis  neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder [Texte imprimé et/ou numérique] / J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur . - p.1088-1100. Langues : Anglais (eng) in Autism Research > 14-6 (June 2021) . - p.1088-1100 Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics  Autism Spectrum Disorder/genetics  DNA Copy Number Variations  Exome  Genetic Predisposition to Disease/genetics  Humans  Nerve Tissue Proteins/genetics  Receptors, Cell Surface  Lrrc40  Plxna2  autism spectrum disorder  diagnosis  neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

Heritability of quantitative autism spectrum traits in adults: A family-based study / S. C. TAYLOR in Autism Research, 14-8 (August 2021)  

Public ISBD [article]  inAutism Research > 14-8 (August 2021) . - p.1543-1553 Titre : Heritability of quantitative autism spectrum traits in adults: A family-based study Type de document : Texte imprimé et/ou numérique Auteurs : S. C. TAYLOR, Auteur ; S. STEEMAN, Auteur ; B. N. GEHRINGER, Auteur ; H. C. DOW, Auteur ; A. LANGER, Auteur ; E. RAWOT, Auteur ; L. PEREZ, Auteur ; M. GOODMAN, Auteur ; Z. SMERNOFF, Auteur ; M. GREWAL, Auteur ; O. ESHRAGHI, Auteur ; Ashley A. PALLATHRA, Auteur ; C. OKSAS, Auteur ; M. MENDEZ, Auteur ; Ruben C. GUR, Auteur ; D. J. RADER, Auteur ; M. BUCAN, Auteur ; Laura ALMASY, Auteur ; Edward S. BRODKIN, Auteur Article en page(s) : p.1543-1553 Langues : Anglais (eng) Mots-clés : Adult  Autism Spectrum Disorder/genetics  Autistic Disorder  Executive Function  Humans  Phenotype  Surveys and Questionnaires  adult  autism spectrum disorder  family studies  heritability  phenotype  quantitative trait Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) comprises a multi-dimensional set of quantitative behavioral traits expressed along a continuum in autistic and neurotypical individuals. ASD diagnosis-a dichotomous trait-is known to be highly heritable and has been used as the phenotype for most ASD genetic studies. But less is known about the heritability of autism spectrum quantitative traits, especially in adults, an important prerequisite for gene discovery. We sought to measure the heritability of many autism-relevant quantitative traits in adults high in autism spectrum traits and their extended family members. Among adults high in autism spectrum traits (n = 158) and their extended family members (n = 245), we calculated univariate and bivariate heritability estimates for 19 autism spectrum traits across several behavioral domains. We found nearly all tested autism spectrum quantitative traits to be significantly heritable (h(2)  = 0.24-0.79), including overall ASD traits, restricted repetitive behaviors, broader autism phenotype traits, social anxiety, and executive functioning. The degree of shared heritability varied based on method and specificity of the assessment measure. We found high shared heritability for the self-report measures and for most of the informant-report measures, with little shared heritability among performance-based cognition tasks. These findings suggest that many autism spectrum quantitative traits would be good, feasible candidates for future genetics studies, allowing for an increase in the power of autism gene discovery. Our findings suggest that the degree of shared heritability between traits depends on the assessment method (self-report vs. informant-report vs. performance-based tasks), as well as trait-specificity. LAY SUMMARY: We found that the scores from questionnaires and tasks measuring different types of behaviors and abilities related to autism spectrum disorder (ASD) were heritable (strongly influenced by gene variants passed down through a family) among autistic adults and their family members. These findings mean that these scores can be used in future studies interested in identifying specific genes and gene variants that are associated with different behaviors and abilities related with ASD. En ligne : http://dx.doi.org/10.1002/aur.2571 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] Heritability of quantitative autism spectrum traits in adults: A family-based study [Texte imprimé et/ou numérique] / S. C. TAYLOR, Auteur ; S. STEEMAN, Auteur ; B. N. GEHRINGER, Auteur ; H. C. DOW, Auteur ; A. LANGER, Auteur ; E. RAWOT, Auteur ; L. PEREZ, Auteur ; M. GOODMAN, Auteur ; Z. SMERNOFF, Auteur ; M. GREWAL, Auteur ; O. ESHRAGHI, Auteur ; Ashley A. PALLATHRA, Auteur ; C. OKSAS, Auteur ; M. MENDEZ, Auteur ; Ruben C. GUR, Auteur ; D. J. RADER, Auteur ; M. BUCAN, Auteur ; Laura ALMASY, Auteur ; Edward S. BRODKIN, Auteur . - p.1543-1553. Langues : Anglais (eng) in Autism Research > 14-8 (August 2021) . - p.1543-1553 Mots-clés : Adult  Autism Spectrum Disorder/genetics  Autistic Disorder  Executive Function  Humans  Phenotype  Surveys and Questionnaires  adult  autism spectrum disorder  family studies  heritability  phenotype  quantitative trait Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) comprises a multi-dimensional set of quantitative behavioral traits expressed along a continuum in autistic and neurotypical individuals. ASD diagnosis-a dichotomous trait-is known to be highly heritable and has been used as the phenotype for most ASD genetic studies. But less is known about the heritability of autism spectrum quantitative traits, especially in adults, an important prerequisite for gene discovery. We sought to measure the heritability of many autism-relevant quantitative traits in adults high in autism spectrum traits and their extended family members. Among adults high in autism spectrum traits (n = 158) and their extended family members (n = 245), we calculated univariate and bivariate heritability estimates for 19 autism spectrum traits across several behavioral domains. We found nearly all tested autism spectrum quantitative traits to be significantly heritable (h(2)  = 0.24-0.79), including overall ASD traits, restricted repetitive behaviors, broader autism phenotype traits, social anxiety, and executive functioning. The degree of shared heritability varied based on method and specificity of the assessment measure. We found high shared heritability for the self-report measures and for most of the informant-report measures, with little shared heritability among performance-based cognition tasks. These findings suggest that many autism spectrum quantitative traits would be good, feasible candidates for future genetics studies, allowing for an increase in the power of autism gene discovery. Our findings suggest that the degree of shared heritability between traits depends on the assessment method (self-report vs. informant-report vs. performance-based tasks), as well as trait-specificity. LAY SUMMARY: We found that the scores from questionnaires and tasks measuring different types of behaviors and abilities related to autism spectrum disorder (ASD) were heritable (strongly influenced by gene variants passed down through a family) among autistic adults and their family members. These findings mean that these scores can be used in future studies interested in identifying specific genes and gene variants that are associated with different behaviors and abilities related with ASD. En ligne : http://dx.doi.org/10.1002/aur.2571 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1(+/-) mouse model of autism spectrum disorders / Kevin LEE in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 13 p. Titre : Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1(+/-) mouse model of autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Kevin LEE, Auteur ; Yewon JUNG, Auteur ; Yukti VYAS, Auteur ; Imogen SKELTON, Auteur ; Wickliffe C. ABRAHAM, Auteur ; Yi-Ping HSUEH, Auteur ; Johanna M. MONTGOMERY, Auteur Article en page(s) : 13 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Dietary Supplements  Disease Models, Animal  Fear/physiology  Humans  Mice  Microfilament Proteins/metabolism  Nerve Tissue Proteins/genetics  Receptors, N-Methyl-D-Aspartate  Synapses/metabolism  T-Box Domain Proteins/metabolism/pharmacology  Zinc/metabolism/pharmacology  Amygdala  Autism spectrum disorder  Dietary zinc supplementation  Glutamatergic synapses  N-methyl-D-aspartate receptors  T-brain-1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by a dyad of behavioural symptoms-social and communication deficits and repetitive behaviours. Multiple aetiological genetic and environmental factors have been identified as causing or increasing the likelihood of ASD, including serum zinc deficiency. Our previous studies revealed that dietary zinc supplementation can normalise impaired social behaviours, excessive grooming, and heightened anxiety in a Shank3 mouse model of ASD, as well as the amelioration of synapse dysfunction. Here, we have examined the efficacy and breadth of dietary zinc supplementation as an effective therapeutic strategy utilising a non-Shank-related mouse model of ASD-mice with Tbr1 haploinsufficiency. METHODS: We performed behavioural assays, amygdalar slice whole-cell patch-clamp electrophysiology, and immunohistochemistry to characterise the synaptic mechanisms underlying the ASD-associated behavioural deficits observed in Tbr1(+/-) mice and the therapeutic potential of dietary zinc supplementation. Two-way analysis of variance (ANOVA) with ?ídák's post hoc test and one-way ANOVA with Tukey's post hoc multiple comparisons were performed for statistical analysis. RESULTS: Our data show that dietary zinc supplementation prevents impairments in auditory fear memory and social interaction, but not social novelty, in the Tbr1(+/-) mice. Tbr1 haploinsufficiency did not induce excessive grooming nor elevate anxiety in mice. At the synaptic level, dietary zinc supplementation reversed ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) hypofunction and normalised presynaptic function at thalamic-lateral amygdala (LA) synapses that are crucial for auditory fear memory. In addition, the zinc supplemented diet significantly restored the synaptic puncta density of the GluN1 subunit essential for functional NMDARs as well as SHANK3 expression in both the basal and lateral amygdala (BLA) of Tbr1(+/-) mice. LIMITATIONS: The therapeutic effect of dietary zinc supplementation observed in rodent models may not reproduce the same effects in human patients. The effect of dietary zinc supplementation on synaptic function in other brain structures affected by Tbr1 haploinsufficiency including olfactory bulb and anterior commissure will also need to be examined. CONCLUSIONS: Our data further the understanding of the molecular mechanisms underlying the effect of dietary zinc supplementation and verify the efficacy and breadth of its application as a potential treatment strategy for ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00494-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477 [article] Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1(+/-) mouse model of autism spectrum disorders [Texte imprimé et/ou numérique] / Kevin LEE, Auteur ; Yewon JUNG, Auteur ; Yukti VYAS, Auteur ; Imogen SKELTON, Auteur ; Wickliffe C. ABRAHAM, Auteur ; Yi-Ping HSUEH, Auteur ; Johanna M. MONTGOMERY, Auteur . - 13 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 13 p. Mots-clés : Animals  Autism Spectrum Disorder/genetics  Dietary Supplements  Disease Models, Animal  Fear/physiology  Humans  Mice  Microfilament Proteins/metabolism  Nerve Tissue Proteins/genetics  Receptors, N-Methyl-D-Aspartate  Synapses/metabolism  T-Box Domain Proteins/metabolism/pharmacology  Zinc/metabolism/pharmacology  Amygdala  Autism spectrum disorder  Dietary zinc supplementation  Glutamatergic synapses  N-methyl-D-aspartate receptors  T-brain-1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by a dyad of behavioural symptoms-social and communication deficits and repetitive behaviours. Multiple aetiological genetic and environmental factors have been identified as causing or increasing the likelihood of ASD, including serum zinc deficiency. Our previous studies revealed that dietary zinc supplementation can normalise impaired social behaviours, excessive grooming, and heightened anxiety in a Shank3 mouse model of ASD, as well as the amelioration of synapse dysfunction. Here, we have examined the efficacy and breadth of dietary zinc supplementation as an effective therapeutic strategy utilising a non-Shank-related mouse model of ASD-mice with Tbr1 haploinsufficiency. METHODS: We performed behavioural assays, amygdalar slice whole-cell patch-clamp electrophysiology, and immunohistochemistry to characterise the synaptic mechanisms underlying the ASD-associated behavioural deficits observed in Tbr1(+/-) mice and the therapeutic potential of dietary zinc supplementation. Two-way analysis of variance (ANOVA) with ?ídák's post hoc test and one-way ANOVA with Tukey's post hoc multiple comparisons were performed for statistical analysis. RESULTS: Our data show that dietary zinc supplementation prevents impairments in auditory fear memory and social interaction, but not social novelty, in the Tbr1(+/-) mice. Tbr1 haploinsufficiency did not induce excessive grooming nor elevate anxiety in mice. At the synaptic level, dietary zinc supplementation reversed ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) hypofunction and normalised presynaptic function at thalamic-lateral amygdala (LA) synapses that are crucial for auditory fear memory. In addition, the zinc supplemented diet significantly restored the synaptic puncta density of the GluN1 subunit essential for functional NMDARs as well as SHANK3 expression in both the basal and lateral amygdala (BLA) of Tbr1(+/-) mice. LIMITATIONS: The therapeutic effect of dietary zinc supplementation observed in rodent models may not reproduce the same effects in human patients. The effect of dietary zinc supplementation on synaptic function in other brain structures affected by Tbr1 haploinsufficiency including olfactory bulb and anterior commissure will also need to be examined. CONCLUSIONS: Our data further the understanding of the molecular mechanisms underlying the effect of dietary zinc supplementation and verify the efficacy and breadth of its application as a potential treatment strategy for ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00494-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477

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