Generation and basic characterization of a gene-trap knockout mouse model of Scn2a with a substantial reduction of voltage-gated sodium channel Na
Genes, brain, and behavior
Genes Brain Behave 2021 Apr; 20(4):e12725
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.
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; and Yang, Yang, "Generation and basic characterization of a gene-trap knockout mouse model of Scn2a with a substantial reduction of voltage-gated sodium channel Na" (2021). Faculty Research 2021. 293.