Autism-related phenotypes in a heterozygous Scn2aR854Q mouse model and their partial rescue via a potassium channel opener.

The voltage-gated sodium channel NaV1.2 is frequently implicated in neurodevelopmental and neurological disorders, including developmental and epileptic encephalopathy (DEE) and autism spectrum disorder (ASD). Genotype-phenotype studies show that NaV1.2 mutations with mixed gain- (GoF) and loss-of-function (LoF) effects are associated with the most severe clinical outcomes. The R853Q mutation in the second gating charge of Domain II decreases current density by 50-60% and was initially classified as a LoF mutation, likely resulting in reduced neuronal firing. However, this does not fully explain its recurrent association with DEE and severe forms of ASD. Our recent findings indicate that R853Q induces a gating pore current (Igp) in the resting state, introducing a GoF component that may increase cortical neuronal excitability. This mixed GoF/LoF effect may underlie the strong clinical phenotypes observed in patients carrying this mutation. To explore this, we generated a mouse model carrying the orthologous R854Q mutation and performed an initial characterization of this model. Behavioral analyses revealed that heterozygous NaV1.2(R854Q) mice exhibit ASD-like phenotypes, including impaired social interaction and social novelty, repetitive rearing, and increased risk-taking behaviors. In silico modeling suggests that, in cortical neurons, the net effect of the R854Q mutation is a reduction in neuronal excitability due to decreased sodium conductance, although Igp alone increases excitability and partially offsets this reduction. Notably, acute administration of retigabine, a potassium channel opener, rescues specific ASD-related phenotypes, possibly by restoring decreased firing through reduction of slow sodium inactivation. Comparative analysis with Scn2a knockout models, which show similar current reduction, highlights the unique severity of R854Q, suggesting a role of Igp in modulating neurobehavioral outcomes and informing potential therapeutic strategies.