Epilepsy and premature mortality driven by inhibitory neuron dysfunction in a mouse model of <i>SCN1A</i> gain-of-function neurodevelopmental disorder

This study demonstrates that SCN1A gain-of-function mutations can lead to severe epilepsy and premature mortality in mice, with potential lifespan extension observed following treatment with GS967.

Summary and findings

The study investigates a mouse model of SCN1A gain-of-function epilepsy, focusing on the impact of the Scn1a-p.R1636Q variant. Premature mortality was observed in 100% of mutant mice due to spontaneous convulsive seizures. Treatment with the sodium channel blocker GS967 prolonged lifespan, but no specific dosage was reported.

Abstract

<h4>ABSTRACT</h4> The gene most commonly implicated in epilepsy, SCN1A , encodes the neuronal voltage-gated sodium channel subunit NaV1.1. SCN1A variants that reduce sodium current (“loss of function” variants) cause Dravet syndrome, a neurodevelopmental disorder defined by treatment-resistant temperature-sensitive epilepsy with onset at/around 5 months of age, developmental delay/intellectual disability, and features of or formal diagnosis autism. However, an emerging group of variants cause “gain of function” (GoF) effects on NaV1.1 and result in a distinct presentation with earlier onset than Dravet syndrome and prominent movement disorder but without temperature sensitivity. We developed the first mouse model of SCN1A GoF epilepsy with heterozygous Cre-dependent expression of the recurrent patient variant Scn1a -p.R1636Q. Global expression of this variant causes premature mortality in 100% (64/64) of mutant mice between postnatal day 12-18 due to spontaneous, convulsive seizures. Activation of the mutant allele in parvalbumin interneurons ( Dlx5/6-Cre or PV-Cre ), but not excitatory neurons ( Slc17a7-Cre ) or other interneuron subtypes ( VIP-Cre or Sst-Cre ), recapitulates the premature mortality and epilepsy phenotypes. Treatment of Scn1a -p.R1636Q mutant mice with the sodium channel blocker GS967 markedly prolongs lifespan. This work is the first study of SCN1A GoF epilepsy in a preclinical model in vivo . Further investigation in the Scn1a flox(R1636Q) mouse will yield new mechanistic insights into disease mechanisms to drive advances in the treatment of SCN1A GoF epilepsy.

Limitations

Not reported in abstract.

Elsewhere in the VIP (Vasoactive Intestinal Polypeptide) corpus