Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs / Feipeng ZHU in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 9p. Titre : Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs Type de document : Texte imprimé et/ou numérique Auteurs : Feipeng ZHU, Auteur ; Qi SHI, Auteur ; Yong-hui JIANG, Auteur ; Yong Q. ZHANG, Auteur ; Hui ZHAO, Auteur Article en page(s) : 9p. Langues : Anglais (eng) Mots-clés : Humans  Dogs  Animals  Autistic Disorder/genetics  Autism Spectrum Disorder  Nerve Tissue Proteins/genetics/metabolism  Pyramidal Cells/metabolism  Synaptic Transmission/genetics  Prefrontal Cortex  Anxiety  Disease Models, Animal  Autism spectrum disorder  Dog  Excitability  Shank3  Synaptic transmission Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. METHODS: We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. RESULTS: We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. LIMITATIONS: Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. CONCLUSIONS: Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research. En ligne : https://dx.doi.org/10.1186/s13229-024-00587-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs [Texte imprimé et/ou numérique] / Feipeng ZHU, Auteur ; Qi SHI, Auteur ; Yong-hui JIANG, Auteur ; Yong Q. ZHANG, Auteur ; Hui ZHAO, Auteur . - 9p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 9p. Mots-clés : Humans  Dogs  Animals  Autistic Disorder/genetics  Autism Spectrum Disorder  Nerve Tissue Proteins/genetics/metabolism  Pyramidal Cells/metabolism  Synaptic Transmission/genetics  Prefrontal Cortex  Anxiety  Disease Models, Animal  Autism spectrum disorder  Dog  Excitability  Shank3  Synaptic transmission Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. METHODS: We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. RESULTS: We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. LIMITATIONS: Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. CONCLUSIONS: Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research. En ligne : https://dx.doi.org/10.1186/s13229-024-00587-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

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 et/ou numérique 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 et/ou numérique] / 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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A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination / Samuel W. HULBERT in Autism Research, 13-10 (October 2020)  

Public ISBD [article]  inAutism Research > 13-10 (October 2020) . - p.1685-1697 Titre : A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination Type de document : Texte imprimé et/ou numérique Auteurs : Samuel W. HULBERT, Auteur ; Xiaoming WANG, Auteur ; Simisola O. GBADEGESIN, Auteur ; Qiong XU, Auteur ; Xiu XU, Auteur ; Yong-hui JIANG, Auteur Article en page(s) : p.1685-1697 Langues : Anglais (eng) Mots-clés : Asd  Chd8  autism  mouse behavior  mouse models Index. décimale : PER Périodiques Résumé : Mutations in CHD8 are among the most common autism-causing genetic defects identified in human genomics studies. Therefore, many labs have attempted to model this disorder by generating mice with mutations in Chd8. Using a gene trap inserted after Exon 31, we created a novel Chd8 mutant mouse (Chd8(+/E31T) ) and characterized its behavior on several different assays thought to have face validity for the human condition, attempting to model both the core symptoms (repetitive behaviors and social communication impairments) and common comorbidities (motor deficits, anxiety, and intellectual disability). We found that Chd8(+/E31T) mice showed no difference compared to wild-type mice in amount of self-grooming, reproducing the negative finding most other studies have reported. Unlike some of the other published lines, Chd8(+/E31T) mice did not show deficits in the three-chamber test for social novelty preference. A few studies have examined ultrasonic vocalizations in Chd8 mutant mice, but we are the first to report an increase in call length for adult mice. Additionally, we found that in contrast to previous published lines, Chd8(+/E31T) mice displayed no anxiety-like behaviors or learning impairments but showed paradoxically significant improvement in motor function. The inconsistencies in behavioral phenotypes in the Chd8 mutant mice generated by different laboratories poses a challenge for modeling autism spectrum disorder and preclinical studies in mice going forward and warrants further investigation into the molecular consequences of the different mutations in Chd8 and the functional impact on behavior. LAY SUMMARY: Several different mouse models carrying mutations in the Chd8 gene have been created to study the effects of these autism-causing mutations in the laboratory. The current study characterizes a novel Chd8 mutant mouse model as well as summarizes data from previously published Chd8 mutant mice. The inconsistencies between different studies are concerning, but future research into the reasons why these inconsistencies occur may help us understand why patients with various mutations have different degrees of symptom severity. Autism Res 2020, 13: 1685-1697. © 2020 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2353 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=431 [article] A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination [Texte imprimé et/ou numérique] / Samuel W. HULBERT, Auteur ; Xiaoming WANG, Auteur ; Simisola O. GBADEGESIN, Auteur ; Qiong XU, Auteur ; Xiu XU, Auteur ; Yong-hui JIANG, Auteur . - p.1685-1697. Langues : Anglais (eng) in Autism Research > 13-10 (October 2020) . - p.1685-1697 Mots-clés : Asd  Chd8  autism  mouse behavior  mouse models Index. décimale : PER Périodiques Résumé : Mutations in CHD8 are among the most common autism-causing genetic defects identified in human genomics studies. Therefore, many labs have attempted to model this disorder by generating mice with mutations in Chd8. Using a gene trap inserted after Exon 31, we created a novel Chd8 mutant mouse (Chd8(+/E31T) ) and characterized its behavior on several different assays thought to have face validity for the human condition, attempting to model both the core symptoms (repetitive behaviors and social communication impairments) and common comorbidities (motor deficits, anxiety, and intellectual disability). We found that Chd8(+/E31T) mice showed no difference compared to wild-type mice in amount of self-grooming, reproducing the negative finding most other studies have reported. Unlike some of the other published lines, Chd8(+/E31T) mice did not show deficits in the three-chamber test for social novelty preference. A few studies have examined ultrasonic vocalizations in Chd8 mutant mice, but we are the first to report an increase in call length for adult mice. Additionally, we found that in contrast to previous published lines, Chd8(+/E31T) mice displayed no anxiety-like behaviors or learning impairments but showed paradoxically significant improvement in motor function. The inconsistencies in behavioral phenotypes in the Chd8 mutant mice generated by different laboratories poses a challenge for modeling autism spectrum disorder and preclinical studies in mice going forward and warrants further investigation into the molecular consequences of the different mutations in Chd8 and the functional impact on behavior. LAY SUMMARY: Several different mouse models carrying mutations in the Chd8 gene have been created to study the effects of these autism-causing mutations in the laboratory. The current study characterizes a novel Chd8 mutant mouse model as well as summarizes data from previously published Chd8 mutant mice. The inconsistencies between different studies are concerning, but future research into the reasons why these inconsistencies occur may help us understand why patients with various mutations have different degrees of symptom severity. Autism Res 2020, 13: 1685-1697. © 2020 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2353 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=431

Psychometric properties of the Chinese Parent Version of the Autism Spectrum Rating Scale: Rasch analysis / Weili YAN in Autism, 26-7 (October 2022)  

Public ISBD [article]  inAutism > 26-7 (October 2022) . - p.1872-1884 Titre : Psychometric properties of the Chinese Parent Version of the Autism Spectrum Rating Scale: Rasch analysis Type de document : Texte imprimé et/ou numérique Auteurs : Weili YAN, Auteur ; Richard J. SIEGERT, Auteur ; Hao ZHOU, Auteur ; Xiaobing ZOU, Auteur ; Lijie WU, Auteur ; Xuerong LUO, Auteur ; Tingyu LI, Auteur ; Yi HUANG, Auteur ; Hongyan GUAN, Auteur ; Xiang CHEN, Auteur ; Meng MAO, Auteur ; Kun XIA, Auteur ; Lan ZHANG, Auteur ; Erzhen LI, Auteur ; Chunpei LI, Auteur ; Xudong ZHANG, Auteur ; Yuanfeng ZHOU, Auteur ; Andy SHIH, Auteur ; Eric FOMBONNE, Auteur ; Yi ZHENG, Auteur ; Jisheng HAN, Auteur ; Zhongsheng SUN, Auteur ; Yong-hui JIANG, Auteur ; Yi WANG, Auteur Article en page(s) : p.1872-1884 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/diagnosis  Autistic Disorder  Child  China  Humans  Parents  Psychometrics  Reproducibility of Results  Autism Spectrum Rating Scale  Rasch analysis  autism spectrum disorders  parent version  school-age children Index. décimale : PER Périodiques Résumé : The Autism Spectrum Rating Scale is a behavioural rating scale completed by parents and teachers that is useful for identifying children with an autism spectrum disorder. The development of a modified Autism Spectrum Rating Scale suitable for use in China is important for the identification of children in China with an autism spectrum disorder. In this study, we examined the Modified Chinese Autism Spectrum Rating Scale using a statistical technique known as Rasch analysis. Rasch analysis tests whether the questionnaire meets the standards for modern scientific measurement. We used Rasch analysis to examine data from 2013 children in China including 420 diagnosed with an autism spectrum disorder who had been rated by a parent or grandparent. After removing a small number of items (questions), the Modified Chinese Autism Spectrum Rating Scale met the stringent criteria for Rasch measurement. The availability of a reliable and precise tool for assessing behaviours characteristic of an autism spectrum disorder in Chinese children will improve the identification and diagnosis of autism spectrum disorder in China, thus enabling better provision of support services. En ligne : http://dx.doi.org/10.1177/13623613211004054 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=484 [article] Psychometric properties of the Chinese Parent Version of the Autism Spectrum Rating Scale: Rasch analysis [Texte imprimé et/ou numérique] / Weili YAN, Auteur ; Richard J. SIEGERT, Auteur ; Hao ZHOU, Auteur ; Xiaobing ZOU, Auteur ; Lijie WU, Auteur ; Xuerong LUO, Auteur ; Tingyu LI, Auteur ; Yi HUANG, Auteur ; Hongyan GUAN, Auteur ; Xiang CHEN, Auteur ; Meng MAO, Auteur ; Kun XIA, Auteur ; Lan ZHANG, Auteur ; Erzhen LI, Auteur ; Chunpei LI, Auteur ; Xudong ZHANG, Auteur ; Yuanfeng ZHOU, Auteur ; Andy SHIH, Auteur ; Eric FOMBONNE, Auteur ; Yi ZHENG, Auteur ; Jisheng HAN, Auteur ; Zhongsheng SUN, Auteur ; Yong-hui JIANG, Auteur ; Yi WANG, Auteur . - p.1872-1884. Langues : Anglais (eng) in Autism > 26-7 (October 2022) . - p.1872-1884 Mots-clés : Autism Spectrum Disorder/diagnosis  Autistic Disorder  Child  China  Humans  Parents  Psychometrics  Reproducibility of Results  Autism Spectrum Rating Scale  Rasch analysis  autism spectrum disorders  parent version  school-age children Index. décimale : PER Périodiques Résumé : The Autism Spectrum Rating Scale is a behavioural rating scale completed by parents and teachers that is useful for identifying children with an autism spectrum disorder. The development of a modified Autism Spectrum Rating Scale suitable for use in China is important for the identification of children in China with an autism spectrum disorder. In this study, we examined the Modified Chinese Autism Spectrum Rating Scale using a statistical technique known as Rasch analysis. Rasch analysis tests whether the questionnaire meets the standards for modern scientific measurement. We used Rasch analysis to examine data from 2013 children in China including 420 diagnosed with an autism spectrum disorder who had been rated by a parent or grandparent. After removing a small number of items (questions), the Modified Chinese Autism Spectrum Rating Scale met the stringent criteria for Rasch measurement. The availability of a reliable and precise tool for assessing behaviours characteristic of an autism spectrum disorder in Chinese children will improve the identification and diagnosis of autism spectrum disorder in China, thus enabling better provision of support services. En ligne : http://dx.doi.org/10.1177/13623613211004054 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=484

Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice / Xiaoming WANG in Molecular Autism, (April 2014)  

Public ISBD [article]  inMolecular Autism > (April 2014) . - p.1-14 Titre : Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice Type de document : Texte imprimé et/ou numérique Auteurs : Xiaoming WANG, Auteur ; Qiong XU, Auteur ; Alexandra L. BEY, Auteur ; Yoonji LEE, Auteur ; Yong-hui JIANG, Auteur Article en page(s) : p.1-14 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Considerable clinical heterogeneity has been well documented amongst individuals with autism spectrum disorders (ASD). However, little is known about the biological mechanisms underlying phenotypic diversity. Genetic studies have established a strong causal relationship between ASD and molecular defects in the SHANK3 gene. Individuals with various defects of SHANK3 display considerable clinical heterogeneity. Different lines of Shank3 mutant mice with deletions of different portions of coding exons have been reported recently. Variable synaptic and behavioral phenotypes have been reported in these mice, which makes the interpretations for these data complicated without the full knowledge of the complexity of the Shank3 transcript structure. En ligne : http://dx.doi.org/10.1186/2040-2392-5-30 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=276 [article] Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice [Texte imprimé et/ou numérique] / Xiaoming WANG, Auteur ; Qiong XU, Auteur ; Alexandra L. BEY, Auteur ; Yoonji LEE, Auteur ; Yong-hui JIANG, Auteur . - p.1-14. Langues : Anglais (eng) in Molecular Autism > (April 2014) . - p.1-14 Index. décimale : PER Périodiques Résumé : Considerable clinical heterogeneity has been well documented amongst individuals with autism spectrum disorders (ASD). However, little is known about the biological mechanisms underlying phenotypic diversity. Genetic studies have established a strong causal relationship between ASD and molecular defects in the SHANK3 gene. Individuals with various defects of SHANK3 display considerable clinical heterogeneity. Different lines of Shank3 mutant mice with deletions of different portions of coding exons have been reported recently. Variable synaptic and behavioral phenotypes have been reported in these mice, which makes the interpretations for these data complicated without the full knowledge of the complexity of the Shank3 transcript structure. En ligne : http://dx.doi.org/10.1186/2040-2392-5-30 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=276

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