Severe deficiency of the voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Highlights

• •Severe Na_V1.2 deficiency results in enhanced neuronal excitability in adult mice
• •Increased excitability is accompanied by a higher voltage threshold in striatal MSNs
• •Hyperexcitability related to Na_V1.2 deficiency is reversible and autonomous
• •Multiple K⁺ channels, including K_V1.1, have a compensatory reduction in expression

Summary

Scn2a encodes the voltage-gated sodium channel Na_V1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that Na_V1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas Na_V1.2 deficiency impairs neuronal excitability, contributing to autism. However, this paradigm does not explain why ∼20%–30% of individuals with Na_V1.2 deficiency still develop seizures. Here, we report the counterintuitive finding that severe Na_V1.2 deficiency results in increased neuronal excitability. Using a Na_V1.2-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_V1.1. Correspondingly, K_V channel openers alleviate the hyperexcitability of Na_V1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying Na_V1.2 deficiency-related seizures.