Scn2a encodes the voltage-gated sodium channel Na1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that Na1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas Na1.2 deficiency impairs neuronal excitability, contributing to autism. However, this paradigm does not explain why ∼20%-30% of individuals with Na1.2 deficiency still develop seizures. Here, we report the counterintuitive finding that severe Na1.2 deficiency results in increased neuronal excitability. Using a Na1.2-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 K1.1. Correspondingly, K channel openers alleviate the hyperexcitability of Na1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying Na1.2 deficiency-related seizures.
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