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

• Published in: Genes, brain and behavior Vol. 20; no. 4
• Main Authors: Eaton, Muriel, Zhang, Jingliang, Ma, Zhixiong, Park, Anthony C., Lietzke, Emma, Romero, Chloé M., Liu, Yushuang, Coleman, Emily R., Chen, Xiaoling, Xiao, Tiange, Que, Zhefu, Lai, Shirong, Wu, Jiaxiang, Lee, Ji Hea, Palant, Sophia, Nguyen, Huynhvi P., Huang, Zhuo, Skarnes, William C., Koss, Wendy A., Yang, Yang
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2021; John Wiley & Sons, Inc
• Subjects: behavior; Central nervous system; channelopathy; Cold tolerance; genetic variants; gene‐trap knockout; Grooming; Mating behavior; mouse model; Nav1.2; nesting; Nesting behavior; neurodevelopmental disorder; Neurodevelopmental disorders; open field; Open-field behavior; Phenotypes; SCN2A gene; Sodium channels (voltage-gated); voltage‐gated sodium channel
• ISSN: 1601-1848; 1601-183X
• DOI: 10.1111/gbb.12725

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 (Nav1.2) 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 Nav1.2 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 Nav1.2 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 Nav1.2 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. SCN2A, encoding for sodium channel Nav1.2, has emerged as one of the most frequently mutated genes in patients with neurodevelopmental disorders including autism. Conventional knockout mouse models of Scn2a do not display major behavioral deficits to recapitulate severe behavioral abnormalities in humans. Here we report a unique gene‐trap knockout mouse model of Scn2a, which displays a range of abnormal behaviors. This mouse model provides exciting opportunities to study pathophysiology associated with Scn2a deficiency.