Somatostatin-Positive Interneurons Contribute to Seizures in Epileptic Encephalopathy.

epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant , which encodes the voltage-gated sodium channel Na1.6. To date, it is unclear if and how inhibitory interneurons, which express Na1.6, influence disease pathology. Using both sexes of a transgenic mouse model of epileptic encephalopathy, we found that selective expression of the R1872W mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable 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 mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in epileptic encephalopathy, but epilepsy in general. epileptic encephalopathy is a devastating neurological disorder that results from mutations in the sodium channel isoform Na1.6. Inhibitory neurons express Na1.6, yet their contribution to seizure generation in epileptic encephalopathy has not been determined. We show that mice expressing a human-derived variant (R1872W) selectively in somatostatin (SST) interneurons have audiogenic seizures. Physiological recordings from SST interneurons show that mutations lead to an elevated persistent sodium current which drives initial hyperexcitability, followed by premature action potential failure because of depolarization block. Furthermore, chemogenetic activation of WT SST interneurons leads to audiogenic seizure activity. These findings provide new insight into the importance of SST inhibitory interneurons in seizure initiation, not only in epileptic encephalopathy, but for epilepsy broadly.