Severe deficiency of voltage-gated sodium channel Na_V1.2 elevates neuronal excitability in adult mice

Abstract

Scn2a encodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions.

Enhanced slow inactivation contributes to dysfunction of a recurrent SCN2A mutation associated with developmental and epileptic encephalopathy

“…Indeed, compensatory downregulation of K V 1.1 occurs in response to Na V 1.2 deficiency in mice (Zhang et al . 2021). Recent evidence also suggests that the smaller AP amplitude secondary to impaired Na V 1.2 conductance may blunt the driving force for potassium ion conductance, slow repolarization and attenuate afterhyperpolarization (Spratt et al .…”

“…It is conceivable that adaptations by neuronal networks to compensate for diminished Na V 1.2 activity resulting from the R853Q channel will predispose to network hyperactivity and seizures following the emergence of Na V 1.6 at the AIS and axon. Indeed, compensatory downregulation of K V 1.1 occurs in response to Na V 1.2 deficiency in mice (Zhang et al 2021). Recent evidence also suggests that the smaller AP amplitude secondary to impaired Na V 1.2 conductance may blunt the driving force for potassium ion conductance, slow repolarization and attenuate afterhyperpolarization (Spratt et al 2021).…”