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Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus / D. SINCLAIR in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)
[article]
Titre : Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus Type de document : Texte imprimé et/ou numérique Auteurs : D. SINCLAIR, Auteur ; J. CESARE, Auteur ; M. MCMULLEN, Auteur ; G. C. CARLSON, Auteur ; C. G. HAHN, Auteur ; K. E. BORGMANN-WINTER, Auteur Article en page(s) : p.14 Langues : Anglais (eng) Mots-clés : Cortex Dtnbp1 Development Dysbindin GluN2B Hippocampus Nmda Phosphorylation Postsynaptic density Sex difference Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch. METHODS: Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA. RESULTS: Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p < 0.05 and p < 0.01, respectively), higher GluN2B phosphorylation at Y1472 (p < 0.01), and greater abundance of PLCgamma (p < 0.01) and Fyn (p = 0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype x age interaction p < 0.05), which also displayed an increased synaptic GluN2A:GluN1 ratio (p < 0.05) and decreased PLCgamma (p < 0.05) and Fyn (only in females; p < 0.0005) compared to wild-types. CONCLUSIONS: Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLCgamma. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction. En ligne : http://dx.doi.org/10.1186/s11689-016-9148-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348
in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.14[article] Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus [Texte imprimé et/ou numérique] / D. SINCLAIR, Auteur ; J. CESARE, Auteur ; M. MCMULLEN, Auteur ; G. C. CARLSON, Auteur ; C. G. HAHN, Auteur ; K. E. BORGMANN-WINTER, Auteur . - p.14.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.14
Mots-clés : Cortex Dtnbp1 Development Dysbindin GluN2B Hippocampus Nmda Phosphorylation Postsynaptic density Sex difference Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch. METHODS: Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA. RESULTS: Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p < 0.05 and p < 0.01, respectively), higher GluN2B phosphorylation at Y1472 (p < 0.01), and greater abundance of PLCgamma (p < 0.01) and Fyn (p = 0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype x age interaction p < 0.05), which also displayed an increased synaptic GluN2A:GluN1 ratio (p < 0.05) and decreased PLCgamma (p < 0.05) and Fyn (only in females; p < 0.0005) compared to wild-types. CONCLUSIONS: Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLCgamma. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction. En ligne : http://dx.doi.org/10.1186/s11689-016-9148-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish / Josiah D. ZOODSMA in Molecular Autism, 13 (2022)
[article]
Titre : Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish Type de document : Texte imprimé et/ou numérique Auteurs : Josiah D. ZOODSMA, Auteur ; Emma J. KEEGAN, Auteur ; Gabrielle R. MOODY, Auteur ; Ashwin A. BHANDIWAD, Auteur ; Amalia J. NAPOLI, Auteur ; Harold A. BURGESS, Auteur ; Lonnie P. WOLLMUTH, Auteur ; Howard I. SIROTKIN, Auteur Article en page(s) : 38 p. Langues : Anglais (eng) Mots-clés : Animals Codon, Nonsense Glutamic Acid Neurodevelopmental Disorders/genetics Receptors, N-Methyl-D-Aspartate/genetics Zebrafish/genetics Autism spectrum disorders GluN2B NMDA receptors Social behaviors Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD), like many neurodevelopmental disorders, has complex and varied etiologies. Advances in genome sequencing have identified multiple candidate genes associated with ASD, including dozens of missense and nonsense mutations in the NMDAR subunit GluN2B, encoded by GRIN2B. NMDARs are glutamate-gated ion channels with key synaptic functions in excitatory neurotransmission. How alterations in these proteins impact neurodevelopment is poorly understood, in part because knockouts of GluN2B in rodents are lethal. METHODS: Here, we use CRISPR-Cas9 to generate zebrafish lacking GluN2B (grin2B(-/-)). Using these fish, we run an array of behavioral tests and perform whole-brain larval imaging to assay developmental roles and functions of GluN2B. RESULTS: We demonstrate that zebrafish GluN2B displays similar structural and functional properties to human GluN2B. Zebrafish lacking GluN2B (grin2B(-/-)) surprisingly survive into adulthood. Given the prevalence of social deficits in ASD, we assayed social preference in the grin2B(-/-) fish. Wild-type fish develop a strong social preference by 3Â weeks post fertilization. In contrast, grin2B(-/-) fish at this age exhibit significantly reduced social preference. Notably, the lack of GluN2B does not result in a broad disruption of neurodevelopment, as grin2B(-/-) larvae do not show alterations in spontaneous or photic-evoked movements, are capable of prey capture, and exhibit learning. Whole-brain imaging of grin2B(-/-) larvae revealed reduction of an inhibitory neuron marker in the subpallium, a region linked to ASD in humans, but showed that overall brain size and E/I balance in grin2B(-/-) is comparable to wild type. LIMITATIONS: Zebrafish lacking GluN2B, while useful in studying developmental roles of GluN2B, are unlikely to model nuanced functional alterations of human missense mutations that are not complete loss of function. Additionally, detailed mammalian homologies for larval zebrafish brain subdivisions at the age of whole-brain imaging are not fully resolved. CONCLUSIONS: We demonstrate that zebrafish completely lacking the GluN2B subunit of the NMDAR, unlike rodent models, are viable into adulthood. Notably, they exhibit a highly specific deficit in social behavior. As such, this zebrafish model affords a unique opportunity to study the roles of GluN2B in ASD etiologies and establish a disease-relevant in vivo model for future studies. En ligne : http://dx.doi.org/10.1186/s13229-022-00516-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491
in Molecular Autism > 13 (2022) . - 38 p.[article] Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish [Texte imprimé et/ou numérique] / Josiah D. ZOODSMA, Auteur ; Emma J. KEEGAN, Auteur ; Gabrielle R. MOODY, Auteur ; Ashwin A. BHANDIWAD, Auteur ; Amalia J. NAPOLI, Auteur ; Harold A. BURGESS, Auteur ; Lonnie P. WOLLMUTH, Auteur ; Howard I. SIROTKIN, Auteur . - 38 p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 38 p.
Mots-clés : Animals Codon, Nonsense Glutamic Acid Neurodevelopmental Disorders/genetics Receptors, N-Methyl-D-Aspartate/genetics Zebrafish/genetics Autism spectrum disorders GluN2B NMDA receptors Social behaviors Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD), like many neurodevelopmental disorders, has complex and varied etiologies. Advances in genome sequencing have identified multiple candidate genes associated with ASD, including dozens of missense and nonsense mutations in the NMDAR subunit GluN2B, encoded by GRIN2B. NMDARs are glutamate-gated ion channels with key synaptic functions in excitatory neurotransmission. How alterations in these proteins impact neurodevelopment is poorly understood, in part because knockouts of GluN2B in rodents are lethal. METHODS: Here, we use CRISPR-Cas9 to generate zebrafish lacking GluN2B (grin2B(-/-)). Using these fish, we run an array of behavioral tests and perform whole-brain larval imaging to assay developmental roles and functions of GluN2B. RESULTS: We demonstrate that zebrafish GluN2B displays similar structural and functional properties to human GluN2B. Zebrafish lacking GluN2B (grin2B(-/-)) surprisingly survive into adulthood. Given the prevalence of social deficits in ASD, we assayed social preference in the grin2B(-/-) fish. Wild-type fish develop a strong social preference by 3Â weeks post fertilization. In contrast, grin2B(-/-) fish at this age exhibit significantly reduced social preference. Notably, the lack of GluN2B does not result in a broad disruption of neurodevelopment, as grin2B(-/-) larvae do not show alterations in spontaneous or photic-evoked movements, are capable of prey capture, and exhibit learning. Whole-brain imaging of grin2B(-/-) larvae revealed reduction of an inhibitory neuron marker in the subpallium, a region linked to ASD in humans, but showed that overall brain size and E/I balance in grin2B(-/-) is comparable to wild type. LIMITATIONS: Zebrafish lacking GluN2B, while useful in studying developmental roles of GluN2B, are unlikely to model nuanced functional alterations of human missense mutations that are not complete loss of function. Additionally, detailed mammalian homologies for larval zebrafish brain subdivisions at the age of whole-brain imaging are not fully resolved. CONCLUSIONS: We demonstrate that zebrafish completely lacking the GluN2B subunit of the NMDAR, unlike rodent models, are viable into adulthood. Notably, they exhibit a highly specific deficit in social behavior. As such, this zebrafish model affords a unique opportunity to study the roles of GluN2B in ASD etiologies and establish a disease-relevant in vivo model for future studies. En ligne : http://dx.doi.org/10.1186/s13229-022-00516-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491