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

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.