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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.    Electronic supplementary material  The online version of this article (10.1186/s13229-019-0265-5) contains supplementary material, which is available to authorized users.

molecular autism

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