# Treatment of epilepsy and associated comorbidities using stem cell-derived interneurons to correct circuit dysfunction in an animal model of Dravet syndrome

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $33,101

## Abstract

Project Summary
This proposal investigates the hypothesis that stem cell-derived progenitors of GABAergic inhibitory interneurons
will treat epilepsy in a validated mouse model of the devastating epileptic encephalopathy known as Dravet
syndrome (DS). Characterized as an infantile-onset epilepsy that leads to severe autistic-like cognitive
impairment with high rates of sudden unexplained death (SUDEP), DS is caused by a heterozygous loss-of-
function mutation in SCN1A encoding the type 1 voltage-gated sodium channel. Although a mechanistic basis
of the syndrome remains poorly understood, studies using animal models strongly suggest that Scn1a mutations
selectively impair PV and SST inhibitory interneurons, and conditional deletion of Scn1a in forebrain interneurons
was previously shown to fully recapitulate the epileptic phenotype. This selective impairment of interneurons
makes DS a promising target for the development of therapy based on transplantation of exogenous
interneurons, which can migrate long distances from the injection site and integrate synaptically with surrounding
cortical interneurons (IN’s) within host brain. This unique ability has driven the successful use of interneurons
derived from fetal tissue to treat acquired epilepsy in rodent models. However, it remains unclear whether a
rodent model of a genetic epilepsy can be treated effectively with interneurons that are derived from stem cells,
a more clinically applicable viable alternative to fetal cells. Additionally, while the physiological roles of
endogenous PV and SST cells are relatively well established, it remains unknown how engrafted PV- and SST-
fated precursors mature and influence host activity. To address these important questions, we will study the
effect of transplants at the level of single cells, circuits, and whole animals. We hypothesize that mouse
embryonic stem cell (mESC)-derived interneuron transplants will synaptically integrate into the epileptic
brain of DS mice, improve circuit-level disinhibition in vitro, and suppress seizures in vivo. In aim 1, I will
use whole-cell patch-clamp electrophysiology in acute brain slices to determine whether transplanted PV and
SST interneuron transplants demonstrate intrinsic maturity and influence host activity at the level of interneuron
subtype-specific microcircuits. In aim 2, I will assess the inhibitory influence of transplants in vivo by first using
optogenetics and calcium imaging to assess inhibition of endogenous excitatory neurons, and then assessing
the transplants’ effect on seizures in DS mice.

## Key facts

- **NIH application ID:** 10131871
- **Project number:** 5F31NS108622-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nathaniel Phelps Sotuyo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,101
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131871

## Citation

> US National Institutes of Health, RePORTER application 10131871, Treatment of epilepsy and associated comorbidities using stem cell-derived interneurons to correct circuit dysfunction in an animal model of Dravet syndrome (5F31NS108622-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10131871. Licensed CC0.

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