# Elucidating the contribution of interneuron subtypes in Leigh syndrome-related epilepsy

> **NIH NIH F31** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $41,188

## Abstract

PROJECT SUMMARY
This proposal investigates the hypothesis that the two most abundant interneuron subpopulations differentially
contribute to the devastating mitochondria-related epileptic encephaolomyopathy known as Leigh syndrome
(LS). Characterized by infantile-onset epileptic seizures that are often treatment-resistant and highly associated
with premature death, LS is commonly caused by loss-of-function mutations in genes that encode for proteins
within Complex I (CI) of the mitochondrial respiratory chain. Recessive mutations in NADH dehydrogenase
(ubiquinone) iron sulfur protein 4 (NDUFS4), which encodes for a structural protein within CI, is the most common
cause of LS and is often reported in LS cases. Although a mechanistic basis for the syndrome remains poorly
understood, exciting preliminary data using animal models has shown that the conditional deletion of Ndufs4 in
all GABAergic interneurons is sufficient to fully recapitulate the severe and often fatal epilepsy phenotype.
However, the relative contribution of the two most abundant interneuron subtypes; parvalbumin-expressing (PV)
or somatostatin-expressing (SST) interneurons to the epileptic phenotype remains unknown. Additionally, while
the distinct anatomical and physiological characteristics of PV and SST interneurons is relatively well
established, the behavioral and functional consequences of the Ndufs4 KO remain unknown. To address this
knowledge gap, we will study the consequences of the Ndufs4 KO restricted to PV and SST interneurons at the
level of single cells, circuits and whole animals. Based on the intrinsic electrophysiological properties of PV
interneurons and preliminary data, we hypothesize that the conditional deletion of Ndufs4 in only PV interneurons
will lead to a more severe epilepsy phenotype compared to SST interneurons. This fellowship training plan entails
elucidating implications of mitochondrial dysfunction in the context of neurobiology and genetics, using high
quality in vitro and in vivo techniques. Using mouse genetics in combination with behavior, electrophysiology
and imaging techniques, this work has the potential to inform the development of novel, safe and effective
treatment strategies to alleviate treatment-resistant epilepsy and extend the life span of infants suffering from
LS.

## Key facts

- **NIH application ID:** 10401489
- **Project number:** 5F31NS118991-03
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Arena Abena Manning
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,188
- **Award type:** 5
- **Project period:** 2020-07-20 → 2023-07-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401489

## Citation

> US National Institutes of Health, RePORTER application 10401489, Elucidating the contribution of interneuron subtypes in Leigh syndrome-related epilepsy (5F31NS118991-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401489. Licensed CC0.

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