# Identifying a Role for Vasoactive Intestinal Peptide Expressing Interneurons in a Mouse Model of Dravet Syndrome

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $33,248

## Abstract

PROJECT SUMMARY:
I am applying for this NRSA fellowship as an MD/PhD student with the long-term goal of becoming a successful
physician scientist running my own translational neuroscience research lab. This project is designed to give me
the training and experience required towards achievement of this goal.
The goal of the project is to investigate the mechanisms of epilepsy and cognitive impairment in Dravet
syndrome. Dravet syndrome is a severe neurodevelopmental disorder of childhood defined by epilepsy and
autism that is currently without cure or disease-modifying therapy. This syndrome is caused by mutations in the
gene SCN1A, which codes for the voltage gated sodium channel alpha subunit Nav1.1. Based on work in a
mouse model of Dravet Syndrome, it is hypothesized that GABAergic interneurons – particularly the subsets
marked by expression of parvalbumin (PV-INs) and somatostatin (SST-INs) – are selectively impaired, while
excitatory glutamatergic neurons are not affected. Interneurons are classically considered to be inhibitory, so
loss of Nav1.1 in interneurons is thought to cause decreased inhibition in the developing brain with resulting
cognitive impairment and epilepsy. However, interneurons are incredibly diverse in terms of gene expression,
morphology, electrophysiological properties, and synaptic connectivity. Interneurons marked by expression of
vasoactive intestinal peptide (VIP-INs) constitute a third prominent subset of interneurons that form distinct
disinhibitory circuits by primarily targeting other interneurons, and thereby regulate cognitive processing,
attention, and learning, functions which are impaired in Dravet Syndrome. However, no previous study has
investigated whether VIP-INs are impaired in this model. I show preliminary data indicating that VIP-INs do
express Nav1.1 and have impaired excitability in a mouse model of Dravet Syndrome. I hypothesize that this
leads to dysfunction of disinhibitory microcircuits that underlie sensory processing and brain state modulation. In
Aim1, I use slice electrophysiology, immunohistochemistry, and pharmacology to show that VIP-INs in fact
express Nav1.1 and are functionally impaired in Dravet syndrome mice. In Aim 2, I will investigate the effect of
VIP interneuron dysfunction on the activity of a specific sensorimotor circuit in Dravet Syndrome mice using
optogenetics and synaptic physiology. Finally, in Aim 3, I will use two-photon calcium imaging to study cortical
dynamics that depend on VIP-IN activity in awake behaving DS mice in vivo. Results will implicate VIP-IN
dysfunction in the pathogenesis of Dravet syndrome and suggest novel avenues for therapy.

## Key facts

- **NIH application ID:** 10062835
- **Project number:** 5F31NS111803-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kevin Goff
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,248
- **Award type:** 5
- **Project period:** 2019-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062835

## Citation

> US National Institutes of Health, RePORTER application 10062835, Identifying a Role for Vasoactive Intestinal Peptide Expressing Interneurons in a Mouse Model of Dravet Syndrome (5F31NS111803-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10062835. Licensed CC0.

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