Interneuron dysfunction in a new knock-in mouse model of SCN1A GEFS+

Abstract

Advances in genome sequencing have identified over 1300 mutations in the SCN1A sodium channel gene that result in genetic epilepsies. However, how individual mutations within SCN1A produce seizures remains elusive for most mutations. Previous work from our lab has shown that the K1270T (KT) mutation, which is linked to GEFS+ (Genetic Epilepsy with Febrile Seizure plus) in humans, causes reduced firing of GABAergic neurons in a Drosophila knock-in model. To examine the effect of this mutation in mammals, we introduced the equivalent KT mutation into the mouse Scn1a (Scn1a KT ) gene using CRISPR/Cas9. Mouse lines carrying this mutation were examined in two widely used genetic backgrounds, C57BL/6NJ and 129X1/SvJ. In both backgrounds, homozygous mutants had spontaneous seizures and died by postnatal day 23. There was no difference in the lifespan of mice heterozygous for the mutation in either background when compared to wild-type littermates up to 6 months. Heterozygous mutants had heat-induced seizures at ~42 deg. Celsius, a temperature that did not induce seizures in wild-type littermates. In acute hippocampal slices, current-clamp recordings revealed a significant depolarized shift in action potential threshold and reduced action potential amplitude in parvalbumin-expressing inhibitory interneurons in Scn1a KT/+ mice. There was no change in the firing properties of excitatory CA1 pyramidal neurons. Our results indicate that Scn1a KT/+ mice develop seizures, and impaired action potential firing of inhibitory interneurons in Scn1a KT/+ mice may produce hyperexcitability in the hippocampus.

The long-term neurodevelopmental outcomes of febrile seizures and underlying mechanisms

“…However, it remains unclear how most individual mutations in SCN1A lead to seizures. Recent studies have identified a significant depolarizing shift in action potential threshold in parvalbumin expressing inhibitory hippocampal CA1 interneurons but not in firing properties of excitatory pyramidal neurons, suggesting that mutations in the same gene on different cells may cause different consequences (Das et al, 2021). Thus, if single-cell sequencing developed in recent years is used in the future, it will help to identify more specific molecules and also to explain shared mechanisms of different diseases.…”