PROJECT SUMMARY This proposal investigates the hypothesis that the two most abundant interneuron subpopulations differentially contribute to the devastating mitochondria-related epileptic encephaolomyopathy known as Leigh syndrome (LS). Characterized by infantile-onset epileptic seizures that are often treatment-resistant and highly associated with premature death, LS is commonly caused by loss-of-function mutations in genes that encode for proteins within Complex I (CI) of the mitochondrial respiratory chain. Recessive mutations in NADH dehydrogenase (ubiquinone) iron sulfur protein 4 (NDUFS4), which encodes for a structural protein within CI, is the most common cause of LS and is often reported in LS cases. Although a mechanistic basis for the syndrome remains poorly understood, exciting preliminary data using animal models has shown that the conditional deletion of Ndufs4 in all GABAergic interneurons is sufficient to fully recapitulate the severe and often fatal epilepsy phenotype. However, the relative contribution of the two most abundant interneuron subtypes; parvalbumin-expressing (PV) or somatostatin-expressing (SST) interneurons to the epileptic phenotype remains unknown. Additionally, while the distinct anatomical and physiological characteristics of PV and SST interneurons is relatively well established, the behavioral and functional consequences of the Ndufs4 KO remain unknown. To address this knowledge gap, we will study the consequences of the Ndufs4 KO restricted to PV and SST interneurons at the level of single cells, circuits and whole animals. Based on the intrinsic electrophysiological properties of PV interneurons and preliminary data, we hypothesize that the conditional deletion of Ndufs4 in only PV interneurons will lead to a more severe epilepsy phenotype compared to SST interneurons. This fellowship training plan entails elucidating implications of mitochondrial dysfunction in the context of neurobiology and genetics, using high quality in vitro and in vivo techniques. Using mouse genetics in combination with behavior, electrophysiology and imaging techniques, this work has the potential to inform the development of novel, safe and effective treatment strategies to alleviate treatment-resistant epilepsy and extend the life span of infants suffering from LS.