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

PAC1R Genotype to Phenotype Correlations in Autism Spectrum Disorder / M. GOODRICH in Autism Research, 12-2 (February 2019)  

Public ISBD [article]  inAutism Research > 12-2 (February 2019) . - p.200-211 Titre : PAC1R Genotype to Phenotype Correlations in Autism Spectrum Disorder Type de document : Texte imprimé et/ou numérique Auteurs : M. GOODRICH, Auteur ; Anna Chelsea ARMOUR, Auteur ; K. PANCHAPAKESAN, Auteur ; X. YOU, Auteur ; J. DEVANEY, Auteur ; S. KNOBLACH, Auteur ; C. A. W. SULLIVAN, Auteur ; M. J. HERRERO, Auteur ; A. R. GUPTA, Auteur ; C. J. VAIDYA, Auteur ; L. KENWORTHY, Auteur ; Joshua G. CORBIN, Auteur Article en page(s) : p.200-211 Langues : Anglais (eng) Mots-clés : Pac1r  amygdala  autism  genetic modifier  neuroimaging Index. décimale : PER Périodiques Résumé : Amygdala dysfunction has been implicated in numerous neurodevelopmental disorders, including autism spectrum disorder (ASD). Previous studies in mice and humans, respectively, have linked Pac1r/PAC1R function to social behavior and PTSD-susceptibility. Based on this connection to social and emotional processing and the central role played by the amygdala in ASD, we examined a putative role for PAC1R in social deficits in ASD and determined the pattern of gene expression in the developing mouse and human amygdala. We reveal that Pac1r/PAC1R is expressed in both mouse and human amygdala from mid-neurogenesis through early postnatal stages, critical time points when altered brain trajectories are hypothesized to unfold in ASD. We further find that parents of autistic children carrying a previously identified PTSD-risk genotype (CC) report greater reciprocal social deficits compared to those carrying the non-risk GC genotype. Additionally, by exploring resting-state functional connectivity differences in a subsample of the larger behavioral sample, we find higher functional connectivity between the amygdala and right middle temporal gyrus in individuals with the CC risk genotype. Thus, using multimodal approaches, our data reveal that the amygdala-expressed PAC1R gene may be linked to severity of ASD social phenotype and possible alterations in brain connectivity, therefore potentially acting as a modifier of amygdala-related phenotypes. Autism Res 2019, 12: 200-211 (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this multimodal study across mouse and human, we examined expression patterns of Pac1r/PAC1R, a gene implicated in social behavior, and further explored whether a previously identified human PTSD-linked mutation in PAC1R can predict brain connectivity and social deficits in ASD. We find that PAC1R is highly expressed in the both the mouse and human amygdala. Furthermore, our human data suggest that PAC1R genotype is linked to severity of social deficits and functional amygdala connectivity in ASD. En ligne : http://dx.doi.org/10.1002/aur.2051 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=383 [article] PAC1R Genotype to Phenotype Correlations in Autism Spectrum Disorder [Texte imprimé et/ou numérique] / M. GOODRICH, Auteur ; Anna Chelsea ARMOUR, Auteur ; K. PANCHAPAKESAN, Auteur ; X. YOU, Auteur ; J. DEVANEY, Auteur ; S. KNOBLACH, Auteur ; C. A. W. SULLIVAN, Auteur ; M. J. HERRERO, Auteur ; A. R. GUPTA, Auteur ; C. J. VAIDYA, Auteur ; L. KENWORTHY, Auteur ; Joshua G. CORBIN, Auteur . - p.200-211. Langues : Anglais (eng) in Autism Research > 12-2 (February 2019) . - p.200-211 Mots-clés : Pac1r  amygdala  autism  genetic modifier  neuroimaging Index. décimale : PER Périodiques Résumé : Amygdala dysfunction has been implicated in numerous neurodevelopmental disorders, including autism spectrum disorder (ASD). Previous studies in mice and humans, respectively, have linked Pac1r/PAC1R function to social behavior and PTSD-susceptibility. Based on this connection to social and emotional processing and the central role played by the amygdala in ASD, we examined a putative role for PAC1R in social deficits in ASD and determined the pattern of gene expression in the developing mouse and human amygdala. We reveal that Pac1r/PAC1R is expressed in both mouse and human amygdala from mid-neurogenesis through early postnatal stages, critical time points when altered brain trajectories are hypothesized to unfold in ASD. We further find that parents of autistic children carrying a previously identified PTSD-risk genotype (CC) report greater reciprocal social deficits compared to those carrying the non-risk GC genotype. Additionally, by exploring resting-state functional connectivity differences in a subsample of the larger behavioral sample, we find higher functional connectivity between the amygdala and right middle temporal gyrus in individuals with the CC risk genotype. Thus, using multimodal approaches, our data reveal that the amygdala-expressed PAC1R gene may be linked to severity of ASD social phenotype and possible alterations in brain connectivity, therefore potentially acting as a modifier of amygdala-related phenotypes. Autism Res 2019, 12: 200-211 (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this multimodal study across mouse and human, we examined expression patterns of Pac1r/PAC1R, a gene implicated in social behavior, and further explored whether a previously identified human PTSD-linked mutation in PAC1R can predict brain connectivity and social deficits in ASD. We find that PAC1R is highly expressed in the both the mouse and human amygdala. Furthermore, our human data suggest that PAC1R genotype is linked to severity of social deficits and functional amygdala connectivity in ASD. En ligne : http://dx.doi.org/10.1002/aur.2051 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=383

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