Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2a^K1422Emice

Abstract

Pathogenic variants inSCN2Aare associated with a range of neurodevelopmental disorders (NDD). Despite being largely monogenic,SCN2A-related NDD show considerable phenotypic variation and complex genotype-phenotype correlations. Genetic modifiers can contribute to variability in disease phenotypes associated with rare driver mutations. Accordingly, different genetic backgrounds across inbred rodent strains have been shown to influence disease-related phenotypes, including those associated with SCN2A-related NDD. Recently, we developed a mouse model of the variantSCN2A-p.K1422E that was maintained as an isogenic line on the C57BL/6J (B6) strain. Our initial characterization of NDD phenotypes in heterozygousScn2aK1422Emice revealed alterations in anxiety-related behavior and seizure susceptibility. To determine if background strain affects phenotype severity in theScn2aK1422Emouse model, phenotypes of mice on B6 and [DBA/2J x B6]F1 hybrid (F1D2) strains were compared. Convergent evidence from neurobehavioral assays demonstrated lower anxiety-like behavior inScn2aK1422Emice compared to wild-type and further suggested that this effect is more pronounced on the B6 background compared to the F1D2 background. Although there were no strain-dependent differences in occurrence of rare spontaneous seizures, response to the chemoconvulsant kainic acid revealed differences in seizure generalization and lethality risk, with variation based on strain and sex. Continued examination of strain-dependent effects in theScn2aK1422Emouse model could reveal genetic backgrounds with unique susceptibility profiles that would be relevant for future studies on specific traits and enable the identification of highly penetrant phenotypes and modifier genes that could provide clues about the primary pathogenic mechanism of the K1422E variant.