Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons / E. M. A. LEWIS in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 51 p. Titre : Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : E. M. A. LEWIS, Auteur ; K. MEGANATHAN, Auteur ; D. BALDRIDGE, Auteur ; P. GONTARZ, Auteur ; B. ZHANG, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur ; K. L. KROLL, Auteur Article en page(s) : 51 p. Langues : Anglais (eng) Mots-clés : Cortical excitatory neurons  Cortical inhibitory neurons  Gene networks  Multiplex autism  Neurodevelopment  Transcriptomics  iPSC modeling Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. En ligne : http://dx.doi.org/10.1186/s13229-019-0306-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 [article] Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons [Texte imprimé et/ou numérique] / E. M. A. LEWIS, Auteur ; K. MEGANATHAN, Auteur ; D. BALDRIDGE, Auteur ; P. GONTARZ, Auteur ; B. ZHANG, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur ; K. L. KROLL, Auteur . - 51 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 51 p. Mots-clés : Cortical excitatory neurons  Cortical inhibitory neurons  Gene networks  Multiplex autism  Neurodevelopment  Transcriptomics  iPSC modeling Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. En ligne : http://dx.doi.org/10.1186/s13229-019-0306-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414

Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome / T. D. ROGERS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 30p. Titre : Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : T. D. ROGERS, Auteur ; A. M. J. ANACKER, Auteur ; T. M. KERR, Auteur ; C. G. FORSBERG, Auteur ; J. WANG, Auteur ; B. ZHANG, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur Article en page(s) : 30p. Langues : Anglais (eng) Mots-clés : Amygdala  Autism spectrum disorder  Fragile X syndrome  Prefrontal cortex  RNA sequencing  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. En ligne : http://dx.doi.org/10.1186/s13229-017-0148-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome [Texte imprimé et/ou numérique] / T. D. ROGERS, Auteur ; A. M. J. ANACKER, Auteur ; T. M. KERR, Auteur ; C. G. FORSBERG, Auteur ; J. WANG, Auteur ; B. ZHANG, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur . - 30p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 30p. Mots-clés : Amygdala  Autism spectrum disorder  Fragile X syndrome  Prefrontal cortex  RNA sequencing  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. En ligne : http://dx.doi.org/10.1186/s13229-017-0148-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome / M. G. MARISCAL in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 29 p. Titre : Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome Type de document : Texte imprimé et/ou numérique Auteurs : M. G. MARISCAL, Auteur ; Elizabeth BERRY-KRAVIS, Auteur ; Joseph D. BUXBAUM, Auteur ; L. E. ETHRIDGE, Auteur ; R. FILIP-DHIMA, Auteur ; J. H. FOSS-FEIG, Auteur ; A. KOLEVZON, Auteur ; M. E. MODI, Auteur ; M. W. MOSCONI, Auteur ; C. A. NELSON, Auteur ; C. M. POWELL, Auteur ; P. M. SIPER, Auteur ; L. SOORYA, Auteur ; A. THALIATH, Auteur ; A. THURM, Auteur ; B. ZHANG, Auteur ; M. SAHIN, Auteur ; A. R. LEVIN, Auteur Article en page(s) : 29 p. Langues : Anglais (eng) Mots-clés : Cross-frequency coupling  Eeg  Phase bias  Phelan-McDermid syndrome  Power Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid Syndrome (PMS) is a rare condition caused by deletion or mutation of the SHANK3 gene. Individuals with PMS frequently present with intellectual disability, autism spectrum disorder, and other neurodevelopmental challenges. Electroencephalography (EEG) can provide a window into network-level function in PMS. METHODS: Here, we analyze EEG data collected across multiple sites in individuals with PMS (n?=?26) and typically developing individuals (n?=?15). We quantify oscillatory power, alpha-gamma phase-amplitude coupling strength, and phase bias, a measure of the phase of cross frequency coupling thought to reflect the balance of feedforward (bottom-up) and feedback (top-down) activity. RESULTS: We find individuals with PMS display increased alpha-gamma phase bias (U?=?3.841, p? En ligne : http://dx.doi.org/10.1186/s13229-020-00411-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome [Texte imprimé et/ou numérique] / M. G. MARISCAL, Auteur ; Elizabeth BERRY-KRAVIS, Auteur ; Joseph D. BUXBAUM, Auteur ; L. E. ETHRIDGE, Auteur ; R. FILIP-DHIMA, Auteur ; J. H. FOSS-FEIG, Auteur ; A. KOLEVZON, Auteur ; M. E. MODI, Auteur ; M. W. MOSCONI, Auteur ; C. A. NELSON, Auteur ; C. M. POWELL, Auteur ; P. M. SIPER, Auteur ; L. SOORYA, Auteur ; A. THALIATH, Auteur ; A. THURM, Auteur ; B. ZHANG, Auteur ; M. SAHIN, Auteur ; A. R. LEVIN, Auteur . - 29 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 29 p. Mots-clés : Cross-frequency coupling  Eeg  Phase bias  Phelan-McDermid syndrome  Power Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid Syndrome (PMS) is a rare condition caused by deletion or mutation of the SHANK3 gene. Individuals with PMS frequently present with intellectual disability, autism spectrum disorder, and other neurodevelopmental challenges. Electroencephalography (EEG) can provide a window into network-level function in PMS. METHODS: Here, we analyze EEG data collected across multiple sites in individuals with PMS (n?=?26) and typically developing individuals (n?=?15). We quantify oscillatory power, alpha-gamma phase-amplitude coupling strength, and phase bias, a measure of the phase of cross frequency coupling thought to reflect the balance of feedforward (bottom-up) and feedback (top-down) activity. RESULTS: We find individuals with PMS display increased alpha-gamma phase bias (U?=?3.841, p? En ligne : http://dx.doi.org/10.1186/s13229-020-00411-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Social-valence-related increased attention in rett syndrome cynomolgus monkeys: An eye-tracking study / B. ZHANG in Autism Research, 12-11 (November 2019)  

Public ISBD [article]  inAutism Research > 12-11 (November 2019) . - p.1585-1597 Titre : Social-valence-related increased attention in rett syndrome cynomolgus monkeys: An eye-tracking study Type de document : Texte imprimé et/ou numérique Auteurs : B. ZHANG, Auteur ; Z. ZHOU, Auteur ; Y. ZHOU, Auteur ; T. ZHANG, Auteur ; Y. MA, Auteur ; Y. NIU, Auteur ; W. JI, Auteur ; Y. CHEN, Auteur Article en page(s) : p.1585-1597 Langues : Anglais (eng) Mots-clés : Rett syndrome  animal models  attention  cognitive neuroscience  visual Index. décimale : PER Périodiques Résumé : The cognitive phenotypes of Rett syndrome (RTT) remain unclarified compared with the well-defined genetic etiology. Recent clinical studies suggest the eye-tracking method as a promising avenue to quantify the visual phenotypes of the syndrome. The present study explored various aspects of visual attention of the methyl-CpG-binding protein 2 gene mutant RTT monkeys with the eye-tracking procedure. Comprehensive testing paradigms, including social valence comparison (SVC), visual paired comparison (VPC), and social recognition memory (SRM), were utilized to investigate their attentional features to social stimuli with differential valence, the novelty preferences, and short-term recognition memory, respectively. To explore the neurobiological mechanisms underlying the eye-tracking findings, we assessed changes of the brain subregion volumes and neurotransmitter concentrations. Compared with control monkeys, RTT monkeys demonstrated increased viewing on the more salient stare faces than profile faces in the SVC test, and increased viewing on the whole presented images composed of monkey faces in the VPC and SRM tests. Brain imaging revealed reduced bilateral occipital gyrus in RTT monkeys. The exploratory neurotransmitter analyses revealed no significant changes of various neurotransmitter concentrations in the cerebrospinal fluid and blood of RTT monkeys. The eye-tracking results suggested social-valence-related increased attention in RTT monkeys, supplementing the cognitive phenotypes associated with the syndrome. Further investigations from broader perspectives are required to uncover the underlying neurobiological mechanisms. Autism Res 2019, 00: 1-13. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Altered expressions of the methyl-CpG-binding protein 2 (MECP2) gene are usually associated with neurodevelopmental disorders, such as autism spectrum disorders, Rett syndrome (RTT), and so forth. The present eye-tracking study found social-valence-related increased attention in our firstly established MECP2 mutant RTT monkeys. The novel findings supplement the cognitive phenotypes and potentially benefit the behavioral interventions of the RTT syndrome. En ligne : http://dx.doi.org/10.1002/aur.2189 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=411 [article] Social-valence-related increased attention in rett syndrome cynomolgus monkeys: An eye-tracking study [Texte imprimé et/ou numérique] / B. ZHANG, Auteur ; Z. ZHOU, Auteur ; Y. ZHOU, Auteur ; T. ZHANG, Auteur ; Y. MA, Auteur ; Y. NIU, Auteur ; W. JI, Auteur ; Y. CHEN, Auteur . - p.1585-1597. Langues : Anglais (eng) in Autism Research > 12-11 (November 2019) . - p.1585-1597 Mots-clés : Rett syndrome  animal models  attention  cognitive neuroscience  visual Index. décimale : PER Périodiques Résumé : The cognitive phenotypes of Rett syndrome (RTT) remain unclarified compared with the well-defined genetic etiology. Recent clinical studies suggest the eye-tracking method as a promising avenue to quantify the visual phenotypes of the syndrome. The present study explored various aspects of visual attention of the methyl-CpG-binding protein 2 gene mutant RTT monkeys with the eye-tracking procedure. Comprehensive testing paradigms, including social valence comparison (SVC), visual paired comparison (VPC), and social recognition memory (SRM), were utilized to investigate their attentional features to social stimuli with differential valence, the novelty preferences, and short-term recognition memory, respectively. To explore the neurobiological mechanisms underlying the eye-tracking findings, we assessed changes of the brain subregion volumes and neurotransmitter concentrations. Compared with control monkeys, RTT monkeys demonstrated increased viewing on the more salient stare faces than profile faces in the SVC test, and increased viewing on the whole presented images composed of monkey faces in the VPC and SRM tests. Brain imaging revealed reduced bilateral occipital gyrus in RTT monkeys. The exploratory neurotransmitter analyses revealed no significant changes of various neurotransmitter concentrations in the cerebrospinal fluid and blood of RTT monkeys. The eye-tracking results suggested social-valence-related increased attention in RTT monkeys, supplementing the cognitive phenotypes associated with the syndrome. Further investigations from broader perspectives are required to uncover the underlying neurobiological mechanisms. Autism Res 2019, 00: 1-13. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Altered expressions of the methyl-CpG-binding protein 2 (MECP2) gene are usually associated with neurodevelopmental disorders, such as autism spectrum disorders, Rett syndrome (RTT), and so forth. The present eye-tracking study found social-valence-related increased attention in our firstly established MECP2 mutant RTT monkeys. The novel findings supplement the cognitive phenotypes and potentially benefit the behavioral interventions of the RTT syndrome. En ligne : http://dx.doi.org/10.1002/aur.2189 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=411

---

1 (1 - 4 / 4)