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Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism / Thomas C. JARAMILLO in Autism Research, 9-3 (March 2016)
[article]
Titre : Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism Type de document : Texte imprimé et/ou numérique Auteurs : Thomas C. JARAMILLO, Auteur ; Haley E. SPEED, Auteur ; Zhong XUAN, Auteur ; Jeremy M. REIMERS, Auteur ; Shunan LIU, Auteur ; Craig M. POWELL, Auteur Article en page(s) : p.350-375 Langues : Anglais (eng) Mots-clés : autism spectrum disorder Shank3 Phelan-McDermid syndrome mouse model grooming Index. décimale : PER Périodiques Résumé : Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ?0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3e4-9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4-9 heterozygous (HET) and Shank3e4-9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4-9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4-9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4-9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4-9 mutant mouse model of autism. Autism Res 2016, 9: 350–375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1529 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=285
in Autism Research > 9-3 (March 2016) . - p.350-375[article] Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism [Texte imprimé et/ou numérique] / Thomas C. JARAMILLO, Auteur ; Haley E. SPEED, Auteur ; Zhong XUAN, Auteur ; Jeremy M. REIMERS, Auteur ; Shunan LIU, Auteur ; Craig M. POWELL, Auteur . - p.350-375.
Langues : Anglais (eng)
in Autism Research > 9-3 (March 2016) . - p.350-375
Mots-clés : autism spectrum disorder Shank3 Phelan-McDermid syndrome mouse model grooming Index. décimale : PER Périodiques Résumé : Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ?0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3e4-9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4-9 heterozygous (HET) and Shank3e4-9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4-9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4-9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4-9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4-9 mutant mouse model of autism. Autism Res 2016, 9: 350–375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1529 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=285 Copy number variations of SHANK3 and related sensory profiles in Egyptian children with autism spectrum disorder / Nagwa A. MEGUID in Research in Autism Spectrum Disorders, 75 (July 2020)
[article]
Titre : Copy number variations of SHANK3 and related sensory profiles in Egyptian children with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Nagwa A. MEGUID, Auteur ; Ola M. EID, Auteur ; Mona REDA, Auteur ; Dina Y. ELALFY, Auteur ; Fatma HUSSEIN, Auteur Article en page(s) : p.101558 Langues : Anglais (eng) Mots-clés : Autism Copy number variations SHANK3 Sensory profiles MLPA Index. décimale : PER Périodiques Résumé : Background Current estimates indicate that >80 % of children with autism spectrum disorder (ASD) exhibit concomitant sensory processing problems and hyper- or hypo-reactivity to sensory input. These are now included as diagnostic criteria for ASD in the Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition. Chromosomal rearrangements, copy number variations (CNVs), and coding sequence variants involving >100 genes have been identified in patients with ASD. Studying the CNVs of one such gene, SHANK3, and the associated phenotype in patients with ASD could provide insights that will guide future ASD treatments and interventions. Objective To assess SHANK3 CNVs in children with ASD and investigate their sensory processing patterns using the Short Sensory Profile (SSP). Subjects and methods Forty children with ASD were assessed using the Autism Diagnostic Interview-Revised. SSP was used to evaluate atypical sensory behavior, e.g., hyper- or hypo-reactivity to sensory input or unusual sensory interests. SHANK3 CNVs were assessed in these children using Multiplex Ligation-dependent Probe Amplification. Results Of the 40 cases, 77.5 % showed sensory reactivity symptoms. The greatest difference from normality was observed in the under-responsive/seeks sensation domain, followed by the tactile sensitivity domain, whereas hypo-activity (low-energy/weak domain) was closest to normal. The sensory reactivity symptoms were significantly correlated with the severity of ASD. However, only three of the 40 cases had de novo duplications at 22q13.33. The duplications included SHANK3 in two of the cases and only the distal flanking region of SHANK3 in the third case. All three duplication cases also showed symptoms associated with the low-energy/weak domain. Conclusion We found that children with ASD exhibited sensory processing problems. The SHANK3 copy number gains found demonstrate the gene dosage effect of SHANK3 in ASD pathogenesis. This study adds to the growing understanding of 22q13 duplications that include SHANK3. En ligne : https://doi.org/10.1016/j.rasd.2020.101558 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=426
in Research in Autism Spectrum Disorders > 75 (July 2020) . - p.101558[article] Copy number variations of SHANK3 and related sensory profiles in Egyptian children with autism spectrum disorder [Texte imprimé et/ou numérique] / Nagwa A. MEGUID, Auteur ; Ola M. EID, Auteur ; Mona REDA, Auteur ; Dina Y. ELALFY, Auteur ; Fatma HUSSEIN, Auteur . - p.101558.
Langues : Anglais (eng)
in Research in Autism Spectrum Disorders > 75 (July 2020) . - p.101558
Mots-clés : Autism Copy number variations SHANK3 Sensory profiles MLPA Index. décimale : PER Périodiques Résumé : Background Current estimates indicate that >80 % of children with autism spectrum disorder (ASD) exhibit concomitant sensory processing problems and hyper- or hypo-reactivity to sensory input. These are now included as diagnostic criteria for ASD in the Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition. Chromosomal rearrangements, copy number variations (CNVs), and coding sequence variants involving >100 genes have been identified in patients with ASD. Studying the CNVs of one such gene, SHANK3, and the associated phenotype in patients with ASD could provide insights that will guide future ASD treatments and interventions. Objective To assess SHANK3 CNVs in children with ASD and investigate their sensory processing patterns using the Short Sensory Profile (SSP). Subjects and methods Forty children with ASD were assessed using the Autism Diagnostic Interview-Revised. SSP was used to evaluate atypical sensory behavior, e.g., hyper- or hypo-reactivity to sensory input or unusual sensory interests. SHANK3 CNVs were assessed in these children using Multiplex Ligation-dependent Probe Amplification. Results Of the 40 cases, 77.5 % showed sensory reactivity symptoms. The greatest difference from normality was observed in the under-responsive/seeks sensation domain, followed by the tactile sensitivity domain, whereas hypo-activity (low-energy/weak domain) was closest to normal. The sensory reactivity symptoms were significantly correlated with the severity of ASD. However, only three of the 40 cases had de novo duplications at 22q13.33. The duplications included SHANK3 in two of the cases and only the distal flanking region of SHANK3 in the third case. All three duplication cases also showed symptoms associated with the low-energy/weak domain. Conclusion We found that children with ASD exhibited sensory processing problems. The SHANK3 copy number gains found demonstrate the gene dosage effect of SHANK3 in ASD pathogenesis. This study adds to the growing understanding of 22q13 duplications that include SHANK3. En ligne : https://doi.org/10.1016/j.rasd.2020.101558 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=426 Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations / S. DE RUBEIS in Molecular Autism, 9 (2018)
[article]
Titre : Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations Type de document : Texte imprimé et/ou numérique Auteurs : S. DE RUBEIS, Auteur ; P. M. SIPER, Auteur ; A. DURKIN, Auteur ; J. WEISSMAN, Auteur ; F. MURATET, Auteur ; Danielle B. HALPERN, Auteur ; M. D. P. TRELLES, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; A. Ting WANG, Auteur ; J. L. HOLDER, Auteur ; Catalina BETANCUR, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur Article en page(s) : 31p. Langues : Anglais (eng) Mots-clés : Adolescent Adult Child Child, Preschool Chromosome Deletion Chromosome Disorders/genetics/pathology Chromosomes, Human, Pair 22/genetics Female Haploinsufficiency Humans Male Nerve Tissue Proteins/genetics Phenotype Point Mutation 22q13 deletion syndrome Autism spectrum disorder Intellectual disability Phelan-McDermid syndrome shank3 Sequence variants Index. décimale : PER Périodiques Résumé : Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods: We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results: SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions: Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3. En ligne : https://dx.doi.org/10.1186/s13229-018-0205-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371
in Molecular Autism > 9 (2018) . - 31p.[article] Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations [Texte imprimé et/ou numérique] / S. DE RUBEIS, Auteur ; P. M. SIPER, Auteur ; A. DURKIN, Auteur ; J. WEISSMAN, Auteur ; F. MURATET, Auteur ; Danielle B. HALPERN, Auteur ; M. D. P. TRELLES, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; A. Ting WANG, Auteur ; J. L. HOLDER, Auteur ; Catalina BETANCUR, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur . - 31p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 31p.
Mots-clés : Adolescent Adult Child Child, Preschool Chromosome Deletion Chromosome Disorders/genetics/pathology Chromosomes, Human, Pair 22/genetics Female Haploinsufficiency Humans Male Nerve Tissue Proteins/genetics Phenotype Point Mutation 22q13 deletion syndrome Autism spectrum disorder Intellectual disability Phelan-McDermid syndrome shank3 Sequence variants Index. décimale : PER Périodiques Résumé : Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods: We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results: SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions: Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3. En ligne : https://dx.doi.org/10.1186/s13229-018-0205-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice / Kyung Ah HAN in Molecular Autism, 11 (2020)
[article]
Titre : Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice Type de document : Texte imprimé et/ou numérique Auteurs : Kyung Ah HAN, Auteur ; Taek Han YOON, Auteur ; Jungsu SHIN, Auteur ; Ji Won UM, Auteur ; Jaewon KO, Auteur Langues : Anglais (eng) Mots-clés : Autism Shank2 Shank3 Social cooperation Social dominance Tube test Index. décimale : PER Périodiques Résumé : BACKGROUND: Recent progress in genomics has contributed to the identification of a large number of autism spectrum disorder (ASD) risk genes, many of which encode synaptic proteins. Our understanding of ASDs has advanced rapidly, partly owing to the development of numerous animal models. Extensive characterizations using a variety of behavioral batteries that analyze social behaviors have shown that a subset of engineered mice that model mutations in genes encoding Shanks, a family of excitatory postsynaptic scaffolding proteins, exhibit autism-like behaviors. Although these behavioral assays have been useful in identifying deficits in simple social behaviors, alterations in complex social behaviors remain largely untested. METHODS: Two syndromic ASD mouse models-Shank2 constitutive knockout [KO] mice and Shank3 constitutive KO mice-were examined for alterations in social dominance and social cooperative behaviors using tube tests and automated cooperation tests. Upon naïve and salient behavioral experience, expression levels of c-Fos were analyzed as a proxy for neural activity across diverse brain areas, including the medial prefrontal cortex (mPFC) and a number of subcortical structures. FINDINGS: As previously reported, Shank2 KO mice showed deficits in sociability, with intact social recognition memory, whereas Shank3 KO mice displayed no overt phenotypes. Strikingly, the two Shank KO mouse models exhibited diametrically opposed alterations in social dominance and cooperative behaviors. After a specific social behavioral experience, Shank mutant mice exhibited distinct changes in number of c-Fos(+) neurons in the number of cortical and subcortical brain regions. CONCLUSIONS: Our results underscore the heterogeneity of social behavioral alterations in different ASD mouse models and highlight the utility of testing complex social behaviors in validating neurodevelopmental and neuropsychiatric disorder models. In addition, neural activities at distinct brain regions are likely collectively involved in eliciting complex social behaviors, which are differentially altered in ASD mouse models. En ligne : http://dx.doi.org/10.1186/s13229-020-00392-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438
in Molecular Autism > 11 (2020)[article] Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice [Texte imprimé et/ou numérique] / Kyung Ah HAN, Auteur ; Taek Han YOON, Auteur ; Jungsu SHIN, Auteur ; Ji Won UM, Auteur ; Jaewon KO, Auteur.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020)
Mots-clés : Autism Shank2 Shank3 Social cooperation Social dominance Tube test Index. décimale : PER Périodiques Résumé : BACKGROUND: Recent progress in genomics has contributed to the identification of a large number of autism spectrum disorder (ASD) risk genes, many of which encode synaptic proteins. Our understanding of ASDs has advanced rapidly, partly owing to the development of numerous animal models. Extensive characterizations using a variety of behavioral batteries that analyze social behaviors have shown that a subset of engineered mice that model mutations in genes encoding Shanks, a family of excitatory postsynaptic scaffolding proteins, exhibit autism-like behaviors. Although these behavioral assays have been useful in identifying deficits in simple social behaviors, alterations in complex social behaviors remain largely untested. METHODS: Two syndromic ASD mouse models-Shank2 constitutive knockout [KO] mice and Shank3 constitutive KO mice-were examined for alterations in social dominance and social cooperative behaviors using tube tests and automated cooperation tests. Upon naïve and salient behavioral experience, expression levels of c-Fos were analyzed as a proxy for neural activity across diverse brain areas, including the medial prefrontal cortex (mPFC) and a number of subcortical structures. FINDINGS: As previously reported, Shank2 KO mice showed deficits in sociability, with intact social recognition memory, whereas Shank3 KO mice displayed no overt phenotypes. Strikingly, the two Shank KO mouse models exhibited diametrically opposed alterations in social dominance and cooperative behaviors. After a specific social behavioral experience, Shank mutant mice exhibited distinct changes in number of c-Fos(+) neurons in the number of cortical and subcortical brain regions. CONCLUSIONS: Our results underscore the heterogeneity of social behavioral alterations in different ASD mouse models and highlight the utility of testing complex social behaviors in validating neurodevelopmental and neuropsychiatric disorder models. In addition, neural activities at distinct brain regions are likely collectively involved in eliciting complex social behaviors, which are differentially altered in ASD mouse models. En ligne : http://dx.doi.org/10.1186/s13229-020-00392-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438 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)
[article]
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 et/ou numérique 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
in Molecular Autism > 13 (2022) . - 35 p.[article] Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice [Texte imprimé et/ou numérique] / 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 Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function / Thomas C. JARAMILLO in Autism Research, 10-1 (January 2017)
PermalinkReduced brain volume and white matter alterations in Shank3-deficient rats / C. E. M. GOLDEN in Autism Research, 14-9 (September 2021)
PermalinkA Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case / C. I. SAMOGY-COSTA in Journal of Neurodevelopmental Disorders, 11-1 (December 2019)
PermalinkClinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome / A. KOLEVZON in Molecular Autism, 13 (2022)
PermalinkCRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors / C. X. LIU in Molecular Autism, 9 (2018)
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