Ethan M. GoldbergGoff, Kevin Mitchell2023-05-222001-01-012022-09-172021-01-012022-09-17https://repository.upenn.edu/handle/20.500.14332/31960GABAergic inhibitory interneurons of the cerebral cortex expressing vasoactive intestinal peptide (VIP-INs) are rapidly emerging as important regulators of network dynamics and normal circuit development. Several recent studies have also identified VIP-IN dysfunction in models of genetically determined neurodevelopmental disorders (NDDs). In this dissertation, we review the known circuit functions of VIP-INs and how they may relate to accumulating evidence implicating VIP-IN dysfunction in the mechanisms of prominent NDDs. We highlight recurring VIP-IN mediated circuit motifs that are shared across cerebral cortical areas, and how VIP-IN activity can shape sensory input, development, and behavior. Ultimately, we extract a set of themes that inform our understanding of how VIP-INs influence pathogenesis of NDDs. We focus on a particularly enticing disease candidate: Dravet Syndrome, a severe NDD characterized by epilepsy, autism spectrum disorder (ASD), and intellectual disability (ID) caused by loss of function variants in SCN1A which codes for the voltage-gated Na+ channel α subunit, Nav1.1. We go on to show that Nav1.1 is expressed in VIP-INs, and loss of a single copy causes VIP-INs to be hypoexcitable in acute brain slices from Scn1a+/- mice. Using this same model, we show that this intrinsic hypoexcitability translates to decreased VIP-IN activity and impaired cortical network dynamics in vivo using two-photon calcium imaging. We find that the above results are replicated when using a conditional deletion of Scn1a in VIP-INs. However, these conditional mutants do not have epilepsy like the global model, but do replicate core features of ASD and ID. This dissociates the roles of VIP-IN dysfunction from potential involvement of other cell types in Dravet pathogenesis. Finally, using publicly available single cell RNA sequencing (scRNA-seq) data from the Allen Institute, we also identify several underexplored disease-associated genes that are highly expressed in VIP-INs. We survey these genes and their shared related disease phenotypes that may broadly implicate VIP-INs in ASD and ID rather than epilepsy. We conclude with a discussion of the relevance of cell type-specific investigations to drive the potential development of therapeutics targeting VIP-INs in the age of genomic diagnosis and precision medicine.191 p.application/pdfKevin Mitchell GoffAutismCircuitsdisinhibitionEpilepsyInterneuronsVIPNeuroscience and NeurobiologyDissertation/Thesis