Africa’s contribution to the science of the COVID-19/SARS-CoV-2 pandemic

Abstract

<h3>Abstract</h3> <i>Scn2a</i> encodes voltage-gated sodium channel Na_V1.2, which mediates neuronal 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. In this paradigm, however, why about a third of patients with Na_V1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe Na_V1.2 deficiency. Using a unique gene-trap knockout mouse model of <i>Scn2a</i>, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in <i>Scn2a</i>-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of <i>Scn2a</i> expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including K_V1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain Na_V1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions. <h3>TEASER</h3> Severe Na_V1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels. <h3>HIGHLIGHTS</h3> Severe Na_V1.2 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; Na_V1.2 deficiency-related hyperexcitability is reversible with the restoration of <i>Scn2a</i> expression, and is autonomous; The expression of the K_V1.1 channel has a compensatory reduction in neurons with Na_V1.2 deficiency, and KV channels openers normalize the neuronal excitability; The enhanced excitability in brain slices translates to elevated <i>in vivo</i> firing commonly associated with seizures.