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SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? / Karina A. KRUTH in Molecular Autism, 11 (2020)
[article]
Titre : SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? Type de document : Texte imprimé et/ou numérique Auteurs : Karina A. KRUTH, Auteur ; Tierney M. GRISOLANO, Auteur ; Christopher A. AHERN, Auteur ; Aislinn J. WILLIAMS, Auteur Article en page(s) : 23 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Cell model Induced pluripotent stem cell NaV1.2 Organoid scn2a SCN2A syndrome Sodium channel Index. décimale : PER Périodiques Résumé : Efforts to identify the causes of autism spectrum disorders have highlighted the importance of both genetics and environment, but the lack of human models for many of these disorders limits researchers' attempts to understand the mechanisms of disease and to develop new treatments. Induced pluripotent stem cells offer the opportunity to study specific genetic and environmental risk factors, but the heterogeneity of donor genetics may obscure important findings. Diseases associated with unusually high rates of autism, such as SCN2A syndromes, provide an opportunity to study specific mutations with high effect sizes in a human genetic context and may reveal biological insights applicable to more common forms of autism. Loss-of-function mutations in the SCN2A gene, which encodes the voltage-gated sodium channel Na(V)1.2, are associated with autism rates up to 50%. Here, we review the findings from experimental models of SCN2A syndromes, including mouse and human cell studies, highlighting the potential role for patient-derived induced pluripotent stem cell technology to identify the molecular and cellular substrates of autism. En ligne : http://dx.doi.org/10.1186/s13229-020-00330-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 23 p.[article] SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? [Texte imprimé et/ou numérique] / Karina A. KRUTH, Auteur ; Tierney M. GRISOLANO, Auteur ; Christopher A. AHERN, Auteur ; Aislinn J. WILLIAMS, Auteur . - 23 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 23 p.
Mots-clés : Autism spectrum disorder Cell model Induced pluripotent stem cell NaV1.2 Organoid scn2a SCN2A syndrome Sodium channel Index. décimale : PER Périodiques Résumé : Efforts to identify the causes of autism spectrum disorders have highlighted the importance of both genetics and environment, but the lack of human models for many of these disorders limits researchers' attempts to understand the mechanisms of disease and to develop new treatments. Induced pluripotent stem cells offer the opportunity to study specific genetic and environmental risk factors, but the heterogeneity of donor genetics may obscure important findings. Diseases associated with unusually high rates of autism, such as SCN2A syndromes, provide an opportunity to study specific mutations with high effect sizes in a human genetic context and may reveal biological insights applicable to more common forms of autism. Loss-of-function mutations in the SCN2A gene, which encodes the voltage-gated sodium channel Na(V)1.2, are associated with autism rates up to 50%. Here, we review the findings from experimental models of SCN2A syndromes, including mouse and human cell studies, highlighting the potential role for patient-derived induced pluripotent stem cell technology to identify the molecular and cellular substrates of autism. En ligne : http://dx.doi.org/10.1186/s13229-020-00330-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity / T. TATSUKAWA in Molecular Autism, 10 (2019)
[article]
Titre : Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity Type de document : Texte imprimé et/ou numérique Auteurs : T. TATSUKAWA, Auteur ; M. RAVEAU, Auteur ; I. OGIWARA, Auteur ; S. HATTORI, Auteur ; H. MIYAMOTO, Auteur ; E. MAZAKI, Auteur ; S. ITOHARA, Auteur ; T. MIYAKAWA, Auteur ; M. MONTAL, Auteur ; K. YAMAKAWA, Auteur Article en page(s) : 15 p. Langues : Anglais (eng) Mots-clés : AMPA receptor Autism Schizophrenia Scn2a Index. décimale : PER Périodiques Résumé : Background: Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated. Methods: We investigated the behavior of mice with a conventional or conditional deletion of Scn2a in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice. Results: Conventional heterozygous Scn2a knockout mice (Scn2a (KO/+)) displayed novelty-induced exploratory hyperactivity and increased rearing. The increased vertical activity was reproduced by heterozygous inactivation of Scn2a in dorsal-telencephalic excitatory neurons but not in inhibitory neurons. Moreover, these phenotypes were rescued by treating Scn2a (KO/+) mice with CX516. Additionally, Scn2a (KO/+) mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2a (KO/+) mice, with an increase in the gamma band. Conclusions: Scn2a (KO/+) mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes. En ligne : http://dx.doi.org/10.1186/s13229-019-0265-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=398
in Molecular Autism > 10 (2019) . - 15 p.[article] Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity [Texte imprimé et/ou numérique] / T. TATSUKAWA, Auteur ; M. RAVEAU, Auteur ; I. OGIWARA, Auteur ; S. HATTORI, Auteur ; H. MIYAMOTO, Auteur ; E. MAZAKI, Auteur ; S. ITOHARA, Auteur ; T. MIYAKAWA, Auteur ; M. MONTAL, Auteur ; K. YAMAKAWA, Auteur . - 15 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 15 p.
Mots-clés : AMPA receptor Autism Schizophrenia Scn2a Index. décimale : PER Périodiques Résumé : Background: Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated. Methods: We investigated the behavior of mice with a conventional or conditional deletion of Scn2a in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice. Results: Conventional heterozygous Scn2a knockout mice (Scn2a (KO/+)) displayed novelty-induced exploratory hyperactivity and increased rearing. The increased vertical activity was reproduced by heterozygous inactivation of Scn2a in dorsal-telencephalic excitatory neurons but not in inhibitory neurons. Moreover, these phenotypes were rescued by treating Scn2a (KO/+) mice with CX516. Additionally, Scn2a (KO/+) mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2a (KO/+) mice, with an increase in the gamma band. Conclusions: Scn2a (KO/+) mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes. En ligne : http://dx.doi.org/10.1186/s13229-019-0265-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=398 Mutations of Voltage-Gated Sodium Channel Genes SCN1A and SCN2A in Epilepsy, Intellectual Disability, and Autism / Kazuhiro YAMAKAWA
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Titre : Mutations of Voltage-Gated Sodium Channel Genes SCN1A and SCN2A in Epilepsy, Intellectual Disability, and Autism Type de document : Texte imprimé et/ou numérique Auteurs : Kazuhiro YAMAKAWA, Auteur Année de publication : 2016 Importance : p.233-251 Langues : Anglais (eng) Mots-clés : Autism Dravet syndrome Epilepsy Intellectual disability Nav1.1 Nav1.2 Parvalbumin inhibitory neuron SCN1A SCN2A Sodium channel Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Mutations of SCN1A and SCN2A were found in a wide spectrum of epilepsies, intellectual disability, and autism. Nav1.1 protein encoded by SCN1A is densely expressed in parvalbumin-positive inhibitory interneurons and moderately in a subpopulation of excitatory neurons. Dravet syndrome model mice (SCN1A+/?) showed epileptic seizure, sudden death, and autistic behavior similar to patients, and conditional knockout mice studies revealed that Nav1.1 haploinsufficiency in inhibitory neurons is the primary cause for those features and that in excitatory neurons it is contrarily ameliorating for seizures and sudden death. Whole-exome sequencing studies on hundreds of autistic patients also showed SCN1A de novo loss of function mutations, but those of SCN2A were far more dominated. SCN2A mutations also appear in patients with epileptic encephalopathies, but those are mostly missense suggesting gain-of-function. Dominant expression of Nav1.2 encoded by SCN2A in excitatory neurons may explain the afebrile nature of the disease and suggest distinct pathological cascades for those with SCN1A mutations. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00015-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 Mutations of Voltage-Gated Sodium Channel Genes SCN1A and SCN2A in Epilepsy, Intellectual Disability, and Autism [Texte imprimé et/ou numérique] / Kazuhiro YAMAKAWA, Auteur . - 2016 . - p.233-251.
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Langues : Anglais (eng)
Mots-clés : Autism Dravet syndrome Epilepsy Intellectual disability Nav1.1 Nav1.2 Parvalbumin inhibitory neuron SCN1A SCN2A Sodium channel Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Mutations of SCN1A and SCN2A were found in a wide spectrum of epilepsies, intellectual disability, and autism. Nav1.1 protein encoded by SCN1A is densely expressed in parvalbumin-positive inhibitory interneurons and moderately in a subpopulation of excitatory neurons. Dravet syndrome model mice (SCN1A+/?) showed epileptic seizure, sudden death, and autistic behavior similar to patients, and conditional knockout mice studies revealed that Nav1.1 haploinsufficiency in inhibitory neurons is the primary cause for those features and that in excitatory neurons it is contrarily ameliorating for seizures and sudden death. Whole-exome sequencing studies on hundreds of autistic patients also showed SCN1A de novo loss of function mutations, but those of SCN2A were far more dominated. SCN2A mutations also appear in patients with epileptic encephalopathies, but those are mostly missense suggesting gain-of-function. Dominant expression of Nav1.2 encoded by SCN2A in excitatory neurons may explain the afebrile nature of the disease and suggest distinct pathological cascades for those with SCN1A mutations. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00015-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 Exemplaires
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