Severe deficiency of the voltage-gated sodium channel Na(V)1.2 elevates neuronal excitability in adult mice

Scn2a encodes the voltage-gated sodium channel Na(V)1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that Na(V)1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas Na(V)1.2 deficiency impairs neuronal excitability, contributing to autism. However, this paradigm does not explain why ~20%–30% of individuals with Na(V)1.2 deficiency still develop seizures. Here, we report the counterintuitive finding that severe Na(V)1.2 deficiency results in increased neuronal excitability. Using a Na(V)1.2-deficient mouse model, we show enhanced intrinsic excitability of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in Scn2a-related seizures. This increased excitability is autonomous and reversible by genetic restoration of Scn2a expression in adult mice. RNA sequencing reveals downregulation of multiple potassium channels, including K(V)1.1. Correspondingly, K(V) channel openers alleviate the hyperexcitability of Na(V)1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying Na(V)1.2 deficiency-related seizures.