Severe deficiency of the voltage-gated sodium channel NaV1.2 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 similar to 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.

Automated summary

Severe Na(V)1.2 deficiency unexpectedly results in increased neuronal excitability, which can be reversed by genetic restoration. This neuronal hyperexcitability may serve as a cellular basis underlying Na(V)1.2 deficiency-related seizures.