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. 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. Conventional heterozygous Scn2a knockout mice (Scn2aKO/+) 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 Scn2aKO/+ mice with CX516. Additionally, Scn2aKO/+ mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2aKO/+ mice, with an increase in the gamma band. Scn2aKO/+ 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.

中文翻译：

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Scn2a单倍型不足的小鼠表现出一系列影响焦虑，社交能力，记忆柔韧性的表型，而安瓿的CX516可以挽救它们的活动过度

编码电压门控钠通道α-II亚基Nav1.2的SCN2A基因的突变与神经系统疾病有关，例如癫痫，自闭症谱系障碍，智力障碍和精神分裂症。然而，这些神经系统缺陷（尤其是社会和精神病学特征）背后的因果关系和致病机制尚待阐明。我们在全面的测试电池组中调查了具有Scn2a常规或条件缺失的小鼠的行为，该电池组包括开放视野，高架迷宫，浅色暗盒，三个隔间，社交优势管，常驻入侵者，超声波发声和恐惧条件测试。我们进一步监测了AMPA受体CX516的正变构调节剂对这些模型小鼠的影响。常规的杂合Scn2a基因敲除小鼠（Scn2aKO / +）表现出新奇诱导的探索性机能亢进和增加的饲养。增加的垂直活性通过背侧脑脊髓兴奋性神经元中Scn2a的杂合失活而得以复制，而在抑制性神经元中则没有。而且，通过用CX516处理Scn2aKO / +小鼠来挽救这些表型。此外，Scn2aKO / +小鼠表现出轻度的社交行为受损，恐惧调节增强和恐惧消退不足。Scn2aKO / +小鼠的内侧前额叶皮层神经元活性增强，γ谱带增加。Scn2aKO / +小鼠表现出在精神分裂症和自闭症谱系障碍模型中通常观察到的表型谱。使用CX516安帕金霉素可改善这些小鼠的活动过度，