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

Modeling autism in non?human primates: Opportunities and challenges / Hui ZHAO in Autism Research, 11-5 (May 2018)  

Public ISBD [article]  inAutism Research > 11-5 (May 2018) . - p.686-694 Titre : Modeling autism in non?human primates: Opportunities and challenges Type de document : Texte imprimé et/ou numérique Auteurs : Hui ZHAO, Auteur ; Yong?Hui JIANG, Auteur ; Q. ZHANG YONG, Auteur Article en page(s) : p.686-694 Langues : Anglais (eng) Mots-clés : non?human primate  autism  social behavior  CRISPR/Cas9 Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and restricted, repetitive patterns of behavior. For more than a decade, genetically?modified, risk factor?induced, as well as naturally occurring rodent models for ASD have been used as the most predominant tools to dissect the molecular and circuitry mechanisms underlying ASD. However, the apparent evolutionary differences in terms of social behavior and brain anatomy between rodents and humans have become an issue of debate regarding the translational value of rodent models for studying ASD. More recently, genome manipulation of non human primates using lentivirus?based gene expression, TALEN and CRISPR/Cas9 mediated gene editing techniques, has been reported. Genetically modified non?human primate models for ASD have been produced and characterized. While the feasibility, value, and exciting opportunities provided by the non?human primate models have been clearly demonstrated, many challenges still remain. Here, we review current progress, discuss the remaining challenges, and highlight the key issues in the development of non?human primate models for ASD research and drug development. Autism Res 2018, 11: 686?694. ? 2018 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Over the last two decades, genetically modified rat and mouse models have been used as the most predominant tools to study mechanisms underlying autism spectrum disorder (ASD). However, the apparent evolutionary differences between rodents and humans limit the translational value of rodent models for studying ASD. Recently, several non?human primate models for ASD have been established and characterized. Here, we review current progress, discuss the challenges, and highlight the key issues in the development of non?human primate models for ASD research and drug development. En ligne : https://doi.org/10.1002/aur.1945 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=363 [article] Modeling autism in non?human primates: Opportunities and challenges [Texte imprimé et/ou numérique] / Hui ZHAO, Auteur ; Yong?Hui JIANG, Auteur ; Q. ZHANG YONG, Auteur . - p.686-694. Langues : Anglais (eng) in Autism Research > 11-5 (May 2018) . - p.686-694 Mots-clés : non?human primate  autism  social behavior  CRISPR/Cas9 Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and restricted, repetitive patterns of behavior. For more than a decade, genetically?modified, risk factor?induced, as well as naturally occurring rodent models for ASD have been used as the most predominant tools to dissect the molecular and circuitry mechanisms underlying ASD. However, the apparent evolutionary differences in terms of social behavior and brain anatomy between rodents and humans have become an issue of debate regarding the translational value of rodent models for studying ASD. More recently, genome manipulation of non human primates using lentivirus?based gene expression, TALEN and CRISPR/Cas9 mediated gene editing techniques, has been reported. Genetically modified non?human primate models for ASD have been produced and characterized. While the feasibility, value, and exciting opportunities provided by the non?human primate models have been clearly demonstrated, many challenges still remain. Here, we review current progress, discuss the remaining challenges, and highlight the key issues in the development of non?human primate models for ASD research and drug development. Autism Res 2018, 11: 686?694. ? 2018 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Over the last two decades, genetically modified rat and mouse models have been used as the most predominant tools to study mechanisms underlying autism spectrum disorder (ASD). However, the apparent evolutionary differences between rodents and humans limit the translational value of rodent models for studying ASD. Recently, several non?human primate models for ASD have been established and characterized. Here, we review current progress, discuss the challenges, and highlight the key issues in the development of non?human primate models for ASD research and drug development. En ligne : https://doi.org/10.1002/aur.1945 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=363

---

1 (1 - 2 / 2)