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.
TEASER Severe NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels.
HIGHLIGHTS
Severe NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice;
Increased neuronal excitability in MSNs is accompanied by elevated voltage threshold;
NaV1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous;
The expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability;
The enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures.
Competing Interest Statement
The authors have declared no competing interest.
