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)  

Public ISBD [article]  inAutism Research > 9-3 (March 2016) . - p.350-375 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 [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

Autism-Related Neuroligin-3 Mutation Alters Social Behavior and Spatial Learning / Thomas C. JARAMILLO in Autism Research, 7-2 (April 2014)  

Public ISBD [article]  inAutism Research > 7-2 (April 2014) . - p.264-272 Titre : Autism-Related Neuroligin-3 Mutation Alters Social Behavior and Spatial Learning Type de document : Texte imprimé et/ou numérique Auteurs : Thomas C. JARAMILLO, Auteur ; Shunan LIU, Auteur ; Ami PETTERSEN, Auteur ; Shari G. BIRNBAUM, Auteur ; Craig M. POWELL, Auteur Article en page(s) : p.264-272 Mots-clés : animal models  behavioral analysis of animal models  intellectual disability  neuroligin  autism Index. décimale : PER Périodiques Résumé : Multiple candidate genes have been identified for autism spectrum disorders. While some of these genes reach genome-wide significance, others, such as the R451C point mutation in the synaptic cell adhesion molecule neuroligin-3, appear to be rare. Interestingly, two brothers with the same R451C point mutation in neuroligin-3 present clinically on seemingly disparate sides of the autism spectrum. These clinical findings suggest genetic background may play a role in modifying the penetrance of a particular autism-associated mutation. Animal models may contribute additional support for such mutations as functionally relevant and can provide mechanistic insights. Previously, in collaboration with the Südhof laboratory, we reported that mice with an R451C substitution in neuroligin-3 displayed social deficits and enhanced spatial learning. While some of these behavioral abnormalities have since been replicated independently in the Südhof laboratory, observations from the Crawley laboratory failed to replicate these findings in a similar neuroligin-3 mutant mouse model and suggested that genetic background may contribute to variation in observations across laboratories. Therefore, we sought to replicate our findings in the neuroligin-3 R451C point mutant knock-in mouse model (NL3R451C) in a different genetic background. We backcrossed our NL3R451C mouse line onto a 129S2/SvPasCrl genetic background and repeated a subset of our previous behavioral testing. NL3R451C mice on a 129S2/SvPasCrl displayed social deficits, enhanced spatial learning, and increased locomotor activity. These data extend our previous findings that NL3R451C mice exhibit autism-relevant behavioral abnormalities and further suggest that different genetic backgrounds can modify this behavioral phenotype through epistatic genetic interactions. En ligne : http://dx.doi.org/10.1002/aur.1362 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=230 [article] Autism-Related Neuroligin-3 Mutation Alters Social Behavior and Spatial Learning [Texte imprimé et/ou numérique] / Thomas C. JARAMILLO, Auteur ; Shunan LIU, Auteur ; Ami PETTERSEN, Auteur ; Shari G. BIRNBAUM, Auteur ; Craig M. POWELL, Auteur . - p.264-272. in Autism Research > 7-2 (April 2014) . - p.264-272 Mots-clés : animal models  behavioral analysis of animal models  intellectual disability  neuroligin  autism Index. décimale : PER Périodiques Résumé : Multiple candidate genes have been identified for autism spectrum disorders. While some of these genes reach genome-wide significance, others, such as the R451C point mutation in the synaptic cell adhesion molecule neuroligin-3, appear to be rare. Interestingly, two brothers with the same R451C point mutation in neuroligin-3 present clinically on seemingly disparate sides of the autism spectrum. These clinical findings suggest genetic background may play a role in modifying the penetrance of a particular autism-associated mutation. Animal models may contribute additional support for such mutations as functionally relevant and can provide mechanistic insights. Previously, in collaboration with the Südhof laboratory, we reported that mice with an R451C substitution in neuroligin-3 displayed social deficits and enhanced spatial learning. While some of these behavioral abnormalities have since been replicated independently in the Südhof laboratory, observations from the Crawley laboratory failed to replicate these findings in a similar neuroligin-3 mutant mouse model and suggested that genetic background may contribute to variation in observations across laboratories. Therefore, we sought to replicate our findings in the neuroligin-3 R451C point mutant knock-in mouse model (NL3R451C) in a different genetic background. We backcrossed our NL3R451C mouse line onto a 129S2/SvPasCrl genetic background and repeated a subset of our previous behavioral testing. NL3R451C mice on a 129S2/SvPasCrl displayed social deficits, enhanced spatial learning, and increased locomotor activity. These data extend our previous findings that NL3R451C mice exhibit autism-relevant behavioral abnormalities and further suggest that different genetic backgrounds can modify this behavioral phenotype through epistatic genetic interactions. En ligne : http://dx.doi.org/10.1002/aur.1362 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=230

Genetic background effects in Neuroligin?3 mutant mice: Minimal behavioral abnormalities on C57 background / Thomas C. JARAMILLO in Autism Research, 11-2 (February 2018)  

Public ISBD [article]  inAutism Research > 11-2 (February 2018) . - p.234-244 Titre : Genetic background effects in Neuroligin?3 mutant mice: Minimal behavioral abnormalities on C57 background Type de document : Texte imprimé et/ou numérique Auteurs : Thomas C. JARAMILLO, Auteur ; Christine Ochoa ESCAMILLA, Auteur ; Shunan LIU, Auteur ; Lauren PECA, Auteur ; Shari G. BIRNBAUM, Auteur ; Craig M. POWELL, Auteur Année de publication : 2018 Article en page(s) : p.234-244 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Neuroligin?3 (NLGN3) is a postsynaptic cell adhesion protein that interacts with presynaptic ligands including neurexin?1 (NRXN1) [Ichtchenko et al., Journal of Biological Chemistry, 271, 2676–2682, 1996]. Mice harboring a mutation in the NLGN3 gene (NL3R451C) mimicking a mutation found in two brothers with autism spectrum disorder (ASD) were previously generated and behaviorally phenotyped for autism?related behaviors. In these NL3R451C mice generated and tested on a hybrid C57BL6J/129S2/SvPasCrl background, we observed enhanced spatial memory and reduced social interaction [Tabuchi et al., Science, 318, 71–76, 2007]. Curiously, an independently generated second line of mice harboring the same mutation on a C57BL6J background exhibited minimal aberrant behavior, thereby providing apparently discrepant results. To investigate the origin of the discrepancy, we previously replicated the original findings of Tabuchi et al. by studying the same NL3R451C mutation on a pure 129S2/SvPasCrl genetic background. Here we complete the behavioral characterization of the NL3R451C mutation on a pure C57BL6J genetic background to determine if background genetics play a role in the discrepant behavioral outcomes involving NL3R451C mice. NL3R451C mutant mice on a pure C57BL6J background did not display spatial memory enhancements or social interaction deficits. We only observed a decreased startle response and mildly increased locomotor activity in these mice suggesting that background genetics influences behavioral outcomes involving the NL3R451C mutation. Autism Res 2018, 11: 234–244. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Behavioral symptoms of autism can be highly variable, even in cases that involve identical genetic mutations. Previous studies in mice with a mutation of the Neuroligin?3 gene showed enhanced learning and social deficits. We replicated these findings on the same and different genetic backgrounds. In this study, however, the same mutation in mice on a different genetic background did not reproduce our previous findings. Our results suggest that genetic background influences behavioral symptoms of this autism?associated mutation. En ligne : https://doi.org/10.1002/aur.1857 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=334 [article] Genetic background effects in Neuroligin?3 mutant mice: Minimal behavioral abnormalities on C57 background [Texte imprimé et/ou numérique] / Thomas C. JARAMILLO, Auteur ; Christine Ochoa ESCAMILLA, Auteur ; Shunan LIU, Auteur ; Lauren PECA, Auteur ; Shari G. BIRNBAUM, Auteur ; Craig M. POWELL, Auteur . - 2018 . - p.234-244. Langues : Anglais (eng) in Autism Research > 11-2 (February 2018) . - p.234-244 Index. décimale : PER Périodiques Résumé : Neuroligin?3 (NLGN3) is a postsynaptic cell adhesion protein that interacts with presynaptic ligands including neurexin?1 (NRXN1) [Ichtchenko et al., Journal of Biological Chemistry, 271, 2676–2682, 1996]. Mice harboring a mutation in the NLGN3 gene (NL3R451C) mimicking a mutation found in two brothers with autism spectrum disorder (ASD) were previously generated and behaviorally phenotyped for autism?related behaviors. In these NL3R451C mice generated and tested on a hybrid C57BL6J/129S2/SvPasCrl background, we observed enhanced spatial memory and reduced social interaction [Tabuchi et al., Science, 318, 71–76, 2007]. Curiously, an independently generated second line of mice harboring the same mutation on a C57BL6J background exhibited minimal aberrant behavior, thereby providing apparently discrepant results. To investigate the origin of the discrepancy, we previously replicated the original findings of Tabuchi et al. by studying the same NL3R451C mutation on a pure 129S2/SvPasCrl genetic background. Here we complete the behavioral characterization of the NL3R451C mutation on a pure C57BL6J genetic background to determine if background genetics play a role in the discrepant behavioral outcomes involving NL3R451C mice. NL3R451C mutant mice on a pure C57BL6J background did not display spatial memory enhancements or social interaction deficits. We only observed a decreased startle response and mildly increased locomotor activity in these mice suggesting that background genetics influences behavioral outcomes involving the NL3R451C mutation. Autism Res 2018, 11: 234–244. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Behavioral symptoms of autism can be highly variable, even in cases that involve identical genetic mutations. Previous studies in mice with a mutation of the Neuroligin?3 gene showed enhanced learning and social deficits. We replicated these findings on the same and different genetic backgrounds. In this study, however, the same mutation in mice on a different genetic background did not reproduce our previous findings. Our results suggest that genetic background influences behavioral symptoms of this autism?associated mutation. En ligne : https://doi.org/10.1002/aur.1857 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=334

Introduction / Craig M. POWELL

Public ISBD in The Autisms / Craig M. POWELL Titre : Introduction Type de document : Texte imprimé et/ou numérique Auteurs : Craig M. POWELL, Auteur ; Lisa M. MONTEGGIA, Auteur Année de publication : 2013 Importance : p.1-3 Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189 in The Autisms / Craig M. POWELL Introduction [Texte imprimé et/ou numérique] / Craig M. POWELL, Auteur ; Lisa M. MONTEGGIA, Auteur . - 2013 . - p.1-3. Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189

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Code-barres	Cote	Support	Localisation	Section	Disponibilité
aucun exemplaire

Neuroligins and neurexins: Bridging the synaptic cleft in autism / Craig M. POWELL

Public ISBD in The Autisms / Craig M. POWELL Titre : Neuroligins and neurexins: Bridging the synaptic cleft in autism Type de document : Texte imprimé et/ou numérique Auteurs : Craig M. POWELL, Auteur ; Antony A. BOUCARD, Auteur Année de publication : 2013 Importance : p.214-239 Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189 in The Autisms / Craig M. POWELL Neuroligins and neurexins: Bridging the synaptic cleft in autism [Texte imprimé et/ou numérique] / Craig M. POWELL, Auteur ; Antony A. BOUCARD, Auteur . - 2013 . - p.214-239. Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189

Exemplaires

Code-barres	Cote	Support	Localisation	Section	Disponibilité
aucun exemplaire

Neuroligins and Neurexins: Synaptic Bridges Implicated in Autism / Craig M. POWELL

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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)  

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Psychometric Study of the Social Responsiveness Scale in Phelan-McDermid Syndrome / Kellie GERGOUDIS in Autism Research, 13-8 (August 2020)  

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PTEN and autism with macrocephaly / Craig M. POWELL

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SHANK gene family and autism / Craig M. POWELL

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The Autisms / Craig M. POWELL

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