Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity

Tetsuya Tatsukawa, Matthieu Raveau, Ikuo Ogiwara, Satoko Takai, Hiroyuki Miyamoto, Emi Mazaki, Shigeyoshi Itohara, Tsuyoshi Miyakawa, Mauricio Montal, Kazuhiro Yamakawa

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number15
JournalMolecular Autism
Volume10
Issue number1
DOIs
Publication statusPublished - 28-03-2019

Fingerprint

Anxiety
Phenotype
Fear
NAV1.2 Voltage-Gated Sodium Channel
Schizophrenia
Social Dominance
Community Psychiatry
Voltage-Gated Sodium Channels
Neurons
Telencephalon
AMPA Receptors
Social Behavior
1-(quinoxalin-6-ylcarbonyl)piperidine
Prefrontal Cortex
Nervous System Diseases
Knockout Mice
Ultrasonics
Intellectual Disability
Epilepsy
Light

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Neuroscience
  • Developmental Biology
  • Psychiatry and Mental health

Cite this

Tatsukawa, Tetsuya ; Raveau, Matthieu ; Ogiwara, Ikuo ; Takai, Satoko ; Miyamoto, Hiroyuki ; Mazaki, Emi ; Itohara, Shigeyoshi ; Miyakawa, Tsuyoshi ; Montal, Mauricio ; Yamakawa, Kazuhiro. / Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity. In: Molecular Autism. 2019 ; Vol. 10, No. 1.
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abstract = "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.",
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Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity. / Tatsukawa, Tetsuya; Raveau, Matthieu; Ogiwara, Ikuo; Takai, Satoko; Miyamoto, Hiroyuki; Mazaki, Emi; Itohara, Shigeyoshi; Miyakawa, Tsuyoshi; Montal, Mauricio; Yamakawa, Kazuhiro.

In: Molecular Autism, Vol. 10, No. 1, 15, 28.03.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity

AU - Tatsukawa, Tetsuya

AU - Raveau, Matthieu

AU - Ogiwara, Ikuo

AU - Takai, Satoko

AU - Miyamoto, Hiroyuki

AU - Mazaki, Emi

AU - Itohara, Shigeyoshi

AU - Miyakawa, Tsuyoshi

AU - Montal, Mauricio

AU - Yamakawa, Kazuhiro

PY - 2019/3/28

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N2 - 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.

AB - 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.

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