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Abstract：
Large-scale genetic studies revealed SCN2A as one of the most frequently mutated genes in patients with neurodevelopmental disorders. SCN2A encodes for the voltage-gated sodium channel isoform 1.2 (Nav 1.2) expressed in the neurons of the central nervous system. Homozygous knockout (null) of Scn2a in mice is perinatal lethal, whereas heterozygous knockout of Scn2a (Scn2a+/- ) results in mild behavior abnormalities. The Nav 1.2 expression level in Scn2a+/- mice is reported to be around 50-60% of the wild-type (WT) level, which indicates that a close to 50% reduction of Nav 1.2 expression may not be sufficient to lead to major behavioral phenotypes in mice. To overcome this barrier, we characterized a novel mouse model of severe Scn2a deficiency using a targeted gene-trap knockout (gtKO) strategy. This approach produces viable homozygous mice (Scn2agtKO/gtKO ) that can survive to adulthood, with about a quarter of Nav 1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in Scn2agtKO/gtKO mice. Notably, Scn2agtKO/gtKO mice have a significantly decreased center duration compared to WT in the open field test, suggesting anxiety-like behaviors in a novel, open space. These mice also have decreased thermal and cold tolerance. Additionally, Scn2agtKO/gtKO mice have increased fix-pattern exploration in the novel object exploration test and a slight increase in grooming, indicating a detectable level of repetitive behaviors. They bury little to no marbles and have decreased interaction with novel objects. These Scn2a gene-trap knockout mice thus provide a unique model to study pathophysiology associated with severe Scn2a deficiency.
摘要：
大规模的遗传研究表明，SCN2A是神经发育障碍患者中最常见的突变基因之一。SCN2A编码在中枢神经系统神经元中表达的电压门控钠通道同工型1.2（Nav1.2）。小鼠中Scn2a的纯合敲除（null）是围产期致死的，而Scn2a的杂合敲除(Scn2a+/-)导致轻度行为异常。据报道，Scn2a+/-小鼠中的Nav1.2表达水平约为野生型（WT）水平的50-60％。这表明接近50%的Nav1.2表达减少可能不足以导致小鼠的主要行为表型。为了克服这个障碍，我们使用靶向基因陷阱敲除（gtKO）策略表征了严重Scn2a缺乏的新型小鼠模型。这种方法产生了活的纯合小鼠（Scn2agtKO/gtKO），可以存活到成年，与WT小鼠相比，Nav1.2表达约为四分之一。在Scn2agtKO/gtKO小鼠中，嵌套和交配等固有行为被严重破坏。值得注意的是,Scn2agtKO/gtKO小鼠在开放场试验中与WT相比，中心持续时间显著减少，在小说中暗示焦虑的行为，开放空间。这些小鼠的热和冷耐受性也降低。此外,Scn2agtKO/gtKO小鼠在新物体探索测试中增加了固定模式探索，并且在修饰上略有增加，表明重复行为的可检测水平。他们几乎没有埋葬大理石，并且减少了与新颖物体的互动。因此,这些Scn2a基因陷阱敲除小鼠提供了研究与严重Scn2a缺乏相关的病理生理学的独特模型。
