Gene therapy with doxycycline-controlled expression of human Kv1.1 reduces neuronal excitability and increases sociability of Scn2a -deficient mice

Genetic loss-of-function (LoF) variants in SCN2A , a gene encoding the voltage-gated sodium channel Nav1.2, have been identified as one of the foremost monogenic causes of autism spectrum disorder (ASD). ASD encompasses a broad spectrum of behavioral phenotypes, with impaired sociability as a core characteristic. We have established Scn2a -deficient mice ( Scn2a ^gt/gt ) to model Scn2a -related ASD and found that this model recapitulates social impairment, exhibiting severe social deficits. Scn2a ^gt/gt mice exhibit neuronal hyperexcitability and a marked global reduction in potassium channel expression, which plays a crucial role in maintaining the resting membrane potential and repolarizing neurons after an action potential. Among these downregulated potassium channels, potassium voltage-gated channel subfamily A member 1 (Kv1.1) was one of the most affected. To explore whether Kv1.1 could be a potential therapeutic target in SCN2A -related ASD, we evaluated the in vivo efficacy of a genetic construct driven by the CaMKIIα promoter that allows for exogenous expression of human Kv1.1 (hKv1.1) in principal neurons. In Scn2a ^gt/gt mice, we found that hKv1.1 expression normalizes neuronal hyperexcitability. Importantly, doxycycline-induced hKv1.1 expression enhances sociability in Scn2a -deficient mice without influencing social behavior in wild-type mice, and this effect was reversed upon doxycycline withdrawal. Overall, we demonstrate the successful use of an inducible AAV-mediated gene delivery system to supplement hKv1.1 expression to mitigate neuronal hyperexcitability and ameliorate social impairments in a mouse model of SCN2A -related ASD. These findings highlight the contribution of Kv1.1 to SCN2A -associated pathophysiology and its potential as a therapeutic target for severe social deficits.