Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Ethan M. Goldberg

Abstract

GABAergic 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.

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