Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life / Jessica A. JIMÉNEZ in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 74 p. Titre : Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life Type de document : texte imprimé Auteurs : Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur Article en page(s) : 74 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Brain overgrowth  Chd8  Endoplasmic reticulum stress  Macrocephaly  Unfolded protein response Index. décimale : PER Périodiques Résumé : BACKGROUND: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. METHODS: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). RESULTS: Chd8(V986*/+) mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8(V986*/+) mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8(V986*/+) crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8(V986*/+) mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8(V986*/+) mice, whereas genes associated with the c-MET signaling pathway were increased in expression. LIMITATIONS: It is unclear whether the transcriptional changes observed with age in Chd8(V986*/+) mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. CONCLUSIONS: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8(V986*/+) mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8(V986*/+) mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00369-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life [texte imprimé] / Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur . - 74 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 74 p. Mots-clés : Autism spectrum disorder  Brain overgrowth  Chd8  Endoplasmic reticulum stress  Macrocephaly  Unfolded protein response Index. décimale : PER Périodiques Résumé : BACKGROUND: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. METHODS: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). RESULTS: Chd8(V986*/+) mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8(V986*/+) mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8(V986*/+) crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8(V986*/+) mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8(V986*/+) mice, whereas genes associated with the c-MET signaling pathway were increased in expression. LIMITATIONS: It is unclear whether the transcriptional changes observed with age in Chd8(V986*/+) mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. CONCLUSIONS: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8(V986*/+) mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8(V986*/+) mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00369-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Correction to: Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life / Jessica A. JIMÉNEZ in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 33 p. Titre : Correction to: Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life Type de document : texte imprimé Auteurs : Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur Article en page(s) : 33 p. Langues : Anglais (eng) Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1186/s13229-021-00438-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Correction to: Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life [texte imprimé] / Jessica A. JIMÉNEZ, Auteur ; Travis S. PTACEK, Auteur ; Alex H. TUTTLE, Auteur ; Ralf S. SCHMID, Auteur ; Sheryl S. MOY, Auteur ; Jeremy M. SIMON, Auteur ; Mark J. ZYLKA, Auteur . - 33 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 33 p. Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1186/s13229-021-00438-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia / Sheryl S. MOY in Journal of Neurodevelopmental Disorders, 1-4 (December 2009)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 1-4 (December 2009) . - p.302-12 Titre : Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia Type de document : texte imprimé Auteurs : Sheryl S. MOY, Auteur ; H. Troy GHASHGHAEI, Auteur ; Randal J. NONNEMAN, Auteur ; Jill M. WEIMER, Auteur ; Yukako YOKOTA, Auteur ; Daekee LEE, Auteur ; Cary LAI, Auteur ; David W. THREADGILL, Auteur ; E.S. ANTON, Auteur Article en page(s) : p.302-12 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Growth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous for an Nrg1 null allele (Nrg1+/-), and mice with conditional ablation of Erbb3 or Erbb4 in the central nervous system, were evaluated for sociability and social novelty preference in a three-chambered choice task. Results showed that deficiencies in NRG1 or ERBB3 significantly enhanced sociability. All of the mutant groups demonstrated a lack of social novelty preference, in contrast to their respective wild-type controls. Effects of NRG1, ERBB3, or ERBB4 deficiency on social behavior could not be attributed to general changes in anxiety-like behavior, activity, or loss of olfactory ability. Nrg1+/- pups did not exhibit changes in isolation-induced ultrasonic vocalizations, a measure of emotional reactivity. Overall, these findings provide evidence that social behavior is mediated by NRG1-ERBB signaling. En ligne : http://dx.doi.org/10.1007/s11689-009-9017-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=342 [article] Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia [texte imprimé] / Sheryl S. MOY, Auteur ; H. Troy GHASHGHAEI, Auteur ; Randal J. NONNEMAN, Auteur ; Jill M. WEIMER, Auteur ; Yukako YOKOTA, Auteur ; Daekee LEE, Auteur ; Cary LAI, Auteur ; David W. THREADGILL, Auteur ; E.S. ANTON, Auteur . - p.302-12. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 1-4 (December 2009) . - p.302-12 Index. décimale : PER Périodiques Résumé : Growth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous for an Nrg1 null allele (Nrg1+/-), and mice with conditional ablation of Erbb3 or Erbb4 in the central nervous system, were evaluated for sociability and social novelty preference in a three-chambered choice task. Results showed that deficiencies in NRG1 or ERBB3 significantly enhanced sociability. All of the mutant groups demonstrated a lack of social novelty preference, in contrast to their respective wild-type controls. Effects of NRG1, ERBB3, or ERBB4 deficiency on social behavior could not be attributed to general changes in anxiety-like behavior, activity, or loss of olfactory ability. Nrg1+/- pups did not exhibit changes in isolation-induced ultrasonic vocalizations, a measure of emotional reactivity. Overall, these findings provide evidence that social behavior is mediated by NRG1-ERBB signaling. En ligne : http://dx.doi.org/10.1007/s11689-009-9017-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=342

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice / Julia S. LORD in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 35 p. Titre : Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice Type de document : texte imprimé Auteurs : Julia S. LORD, Auteur ; Sean M. GAY, Auteur ; Kathryn M. HARPER, Auteur ; Viktoriya D. NIKOLOVA, Auteur ; Kirsten M. SMITH, Auteur ; Sheryl S. MOY, Auteur ; Graham H. DIERING, Auteur Article en page(s) : 35 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Autistic Disorder/genetics  Disease Models, Animal  Female  Male  Mice  Microfilament Proteins  Nerve Tissue Proteins/genetics  Sleep  Autism spectrum disorder  Brain development  Shank3  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3(WT/ΔC) mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. METHODS: We recorded sleep behavior in developing Shank3(ΔC/ΔC), Shank3(WT/ΔC), and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3(WT/ΔC) and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. RESULTS: Male and female Shank3(ΔC/ΔC) mice slept significantly less than wild-type and Shank3(WT/ΔC) siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3(WT/ΔC) mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3(WT/ΔC) subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3(WT/ΔC) subjects had a significant reduction in risk aversion. CON Shank3(WT/ΔC) mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. LIMITATIONS: This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. CONCLUSION: Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility. En ligne : http://dx.doi.org/10.1186/s13229-022-00514-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 [article] Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice [texte imprimé] / Julia S. LORD, Auteur ; Sean M. GAY, Auteur ; Kathryn M. HARPER, Auteur ; Viktoriya D. NIKOLOVA, Auteur ; Kirsten M. SMITH, Auteur ; Sheryl S. MOY, Auteur ; Graham H. DIERING, Auteur . - 35 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 35 p. Mots-clés : Animals  Autism Spectrum Disorder/genetics  Autistic Disorder/genetics  Disease Models, Animal  Female  Male  Mice  Microfilament Proteins  Nerve Tissue Proteins/genetics  Sleep  Autism spectrum disorder  Brain development  Shank3  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3(WT/ΔC) mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. METHODS: We recorded sleep behavior in developing Shank3(ΔC/ΔC), Shank3(WT/ΔC), and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3(WT/ΔC) and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. RESULTS: Male and female Shank3(ΔC/ΔC) mice slept significantly less than wild-type and Shank3(WT/ΔC) siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3(WT/ΔC) mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3(WT/ΔC) subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3(WT/ΔC) subjects had a significant reduction in risk aversion. CON Shank3(WT/ΔC) mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. LIMITATIONS: This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. CONCLUSION: Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility. En ligne : http://dx.doi.org/10.1186/s13229-022-00514-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491

Mouse Behavioral Models for Autism Spectrum Disorders / William C. WETSEL

Public ISBD in The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM Titre : Mouse Behavioral Models for Autism Spectrum Disorders Type de document : texte imprimé Auteurs : William C. WETSEL, Auteur ; Sheryl S. MOY, Auteur ; Yong-hui JIANG, Auteur Année de publication : 2013 Importance : p.363-378 Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorders (ASD) involve impaired development of social interaction and communication, as well as restricted, repetitive, and stereotyped behaviors. ASD has high heritability and certain chromosomal regions and at risk genes are associated with the conditions. Experiments with inbred and outbred rodent models of ASD have revealed procedures that can partially or fully rescue the phenotype; metabotropic GluR5 antagonists appear especially promising in certain models. We summarize behavioral approaches for analyzing mouse models for ASD and review studies in Shank3 mice as a specific example. As SHANK3 variants are identified as a risk factor for autism, mouse lines have been developed with deletions in exons 4–9, exons 13–16, and exon 21 that display, to varying degrees, ASD-like behaviors. Future research with Shank3 lines and other genetic models should help determine the mechanistic basis for both core symptomatologies and divergent behavioral profiles in ASD. Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189 in The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM Mouse Behavioral Models for Autism Spectrum Disorders [texte imprimé] / William C. WETSEL, Auteur ; Sheryl S. MOY, Auteur ; Yong-hui JIANG, Auteur . - 2013 . - p.363-378. Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorders (ASD) involve impaired development of social interaction and communication, as well as restricted, repetitive, and stereotyped behaviors. ASD has high heritability and certain chromosomal regions and at risk genes are associated with the conditions. Experiments with inbred and outbred rodent models of ASD have revealed procedures that can partially or fully rescue the phenotype; metabotropic GluR5 antagonists appear especially promising in certain models. We summarize behavioral approaches for analyzing mouse models for ASD and review studies in Shank3 mice as a specific example. As SHANK3 variants are identified as a risk factor for autism, mouse lines have been developed with deletions in exons 4–9, exons 13–16, and exon 21 that display, to varying degrees, ASD-like behaviors. Future research with Shank3 lines and other genetic models should help determine the mechanistic basis for both core symptomatologies and divergent behavioral profiles in ASD. Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189

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