Global and subtype-specific roles of GABAergic interneurons in Leigh syndrome related epilepsy

Abstract

Leigh syndrome (LS), the most common mitochondrial disease in children, is caused by recessive, loss-of-function mutations in genes that encode for proteins within the mitochondria. Mutations associated with complex I (CI) are commonly associated with LS. Marked by early onset epilepsy, LS is treatment resistant and causes premature death. Recessive mutations in NAD dehydrogenase (ubiquinone) iron sulfur protein 4 (NDUFS4), which encodes for a structural protein within CI, is often reported in LS cases. It has been shown that conditional deletion of Ndufs4 in only GABAergic interneurons recapitulates the severe and fatal epilepsy phenotype, however, a mechanistic basis of LS epilepsy remains unknown. We hypothesized that changes in GABAergic interneuron excitability and expression, due to the Ndufs4 KO, contributes to mechanisms of LS epilepsy. Further, the relative contribution of parvalbumin (PV) and somatostatin (SST) expressing interneurons to the epilepsy phenotype remains unknown. Based on the well-known anatomical and physiological characteristics of PV and SST interneurons, we hypothesized that PV interneurons would contribute more to the epilepsy phenotype than SST interneurons. Using mouse genetics in combination with behavior, electrophysiology, and imaging techniques, we delineated the roles of two interneurons subtypes in mouse models of LS. This work has the potential to inform the development of novel, safe, and effective treatment strategies for epilepsy and mortality associated with LS.