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 ofepileptic encephalopathy, we found that selective expression of the R1872Wmutation 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 ofmutations, 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 inepileptic encephalopathy, but epilepsy in general.epileptic encephalopathy is a devastating neurological disorder that results frommutations in the sodium channel isoform Na1.6. Inhibitory neurons express Na1.6, yet their contribution to seizure generation inepileptic encephalopathy has not been determined. We show that mice expressing a human-derivedvariant (R1872W) selectively in somatostatin (SST) interneurons have audiogenic seizures. Physiological recordings from SST interneurons show thatmutations 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 inepileptic encephalopathy, but for epilepsy broadly. SCN8A SCN8A SCN8A SCN8A SCN8A SCN8A SCN8A de novo SCN8A SCN8A SCN8A SCN8A V V v V SIGNIFICANCE STATEMENT
