Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy

SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A, which encodes the voltage -gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence dis-ease pathology. Using both sexes of a transgenic mouse model of SCN8A epileptic encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audi-ogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperex-citable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of WT SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational model-ing and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A epileptic encephalopathy, but epilepsy in general.

Automated summary

SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A gene encoding NaV1.6 channel, with inhibitory interneurons playing a critical role in seizure generation through hyperexcitability and sensitivity to action potential failure. Aberrantly large persistent sodium currents directly contribute to abnormal physiology in SST interneurons.