# Depolarization block of inhibitory neurons impacts neuronal function in epileptic encephalopathy

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2020 · $27,167

## Abstract

Contact PD/PI: Wengert, Eric Ryan.
PROJECT SUMMARY
SCN8A epileptic encephalopathy is a severe infantile epilepsy syndrome caused by mutations in the SCN8A
gene encoding voltage-gated sodium channel isoform NaV1.6. NaV1.6 is not only expressed in excitatory
neurons, where it is critically involved in action potential (AP) generation and propagation, but it is also
expressed in inhibitory interneurons. Although they make up the minority (~15%) of cortical neurons, inhibitory
interneurons in the neocortex powerfully sculpt network dynamics through various feed-forward, feed-back,
and lateral inhibition circuit motifs. Previous work has implicated NaV1.6 dysfunction with abnormal excitability
in excitatory neurons driven primarily by persistent and resurgent sodium currents. However, there have been
no studies examining the effect of mutant NaV1.6 expression on inhibitory interneuron physiology and the
subsequent contribution of these interneurons to behavioral seizures in SCN8A encephalopathy. This proposal
seeks to test the hypothesis that inhibitory interneuron excitability is reduced in the Scn8aD/+ mouse model of
SCN8A encephalopathy, leading to an increase in overall network excitability. My preliminary data suggest that
somatostatin-positive inhibitory interneurons (SST) have reduced intrinsic excitability at high-firing frequencies
due to entry into depolarization block, and have aberrantly large persistent sodium currents. In aim 1, I will
record WT and Scn8aD/+ and fully characterize the voltage-gated sodium currents, intrinsic excitability, and
alterations in synaptic physiology of the two major interneuron subpopulations: parvalbumin (PV) - and
somatostatin (SST) -positive inhibitory interneurons. This aim will clarify the impact of a gain-of-function
SCN8A mutation on interneuron function and network excitability. In aim 2, I will test the hypothesis that
genetic knock-down of SCN8A specifically in inhibitory interneuron populations using a Cre-dependent shRNA
will rescue the reduction in interneuron excitability, normalize the aberrant sodium channel physiology and
have an impact on seizure frequency and severity in Scn8aD/+ mice. Overall, completion of these aims will
resolve an important question in the field regarding how interneurons contribute to SCN8A encephalopathy and
hopefully generate novel mechanistically-informed approaches to better treat SCN8A encephalopathy.

## Key facts

- **NIH application ID:** 10020197
- **Project number:** 5F31NS115451-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Eric Ryan Wengert
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $27,167
- **Award type:** 5
- **Project period:** 2019-09-06 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020197

## Citation

> US National Institutes of Health, RePORTER application 10020197, Depolarization block of inhibitory neurons impacts neuronal function in epileptic encephalopathy (5F31NS115451-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10020197. Licensed CC0.

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