Generation and basic characterization of a gene‐trap knockout mouse model of Scn2a with a substantial reduction of voltage‐gated sodium channel Nav1.2 expression,Genes, Brain and Behavior

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Generation and basic characterization of a gene‐trap knockout mouse model of Scn2a with a substantial reduction of voltage‐gated sodium channel Nav1.2 expression
Genes, Brain and Behavior ( IF 2.4 ) Pub Date : 2020-12-25 , DOI: 10.1111/gbb.12725
Muriel Eaton _{1,

2} , Jingliang Zhang _{1,

2} , Zhixiong Ma _{1,

2} , Anthony C Park _{1,

2} , Emma Lietzke _{1,

2} , Chloé M Romero _{1,

2} , Yushuang Liu _{1,

2} , Emily R Coleman _{1,

2} , Xiaoling Chen _{1,

2} , Tiange Xiao _{1,

2} , Zhefu Que _{1,

2} , Shirong Lai _{1,

2} , Jiaxiang Wu _{1,

2} , Ji Hea Lee _{1,

2} , Sophia Palant _{1,

2} , Huynhvi P Nguyen _{1,

2} , Zhuo Huang ₃ , William C Skarnes ₄ , Wendy A Koss _{2,

5} , Yang Yang _{1,

2}

Affiliation

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 (Na_v1.2) 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 Na_v1.2 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 Na_v1.2 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 (Scn2a^gtKO/gtKO) that can survive to adulthood, with about a quarter of Na_v1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in Scn2a^gtKO/gtKO mice. Notably, Scn2a^gtKO/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, Scn2a^gtKO/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.

中文翻译：

Scn2a 基因陷阱敲除小鼠模型的生成和基本表征，电压门控钠通道 Nav1.2 表达显着减少

大规模遗传学研究表明， 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亚型 1.2 (Na _v 1.2)。小鼠中Scn2a的纯合敲除（无效）是围产期致死的，而Scn2a的杂合敲除 ( Scn2a ^+/- ) 会导致轻微的行为异常。据报道， Scn2a ^+/-小鼠中的 Na _v 1.2 表达水平约为野生型 (WT) 水平的 50-60%，这表明 Na _v 1.2 表达减少近 50% 可能不足以导致小鼠的主要行为表型。为了克服这一障碍，我们使用靶向基因陷阱敲除（gtKO）策略表征了严重Scn2a缺陷的新型小鼠模型。这种方法产生了可存活的纯合小鼠 ( Scn2a ^gtKO/gtKO )，它们可以存活到成年，与 WT 小鼠相比，Na _v 1.2 表达量约为 1/4。 Scn2a ^gtKO/gtKO小鼠的筑巢和交配等先天行为受到严重破坏。值得注意的是，在开放场地测试中，与 WT 相比， Scn2a ^gtKO/gtKO小鼠的中心持续时间显着缩短，这表明在新的开放空间中存在类似焦虑的行为。这些小鼠的耐热性和耐冷性也降低。此外， Scn2a ^gtKO/gtKO小鼠在新物体探索测试中增加了固定模式探索，并且梳理行为略有增加，表明可检测到重复行为水平。他们很少甚至不埋弹珠，并且与新奇物体的互动也减少了。因此，这些Scn2a基因陷阱敲除小鼠提供了一个独特的模型来研究与严重Scn2a缺陷相关的病理生理学。

更新日期：2020-12-25

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