# Developmental Dysfunction of Parvalbumin Interneurons in Autism Spectrum Disorder

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $46,752

## Abstract

Project Summary
 Recent evidence suggests disruption of GABAergic inhibitory function as a likely mechanism underlying
Autism Spectrum Disorders (ASD). In order to function correctly, neural networks must establish precise and
stable interconnected circuits. Synaptic refinement mediated by GABAergic inhibitory neurons during
development is necessary for the precision of brain function, and thus, developmental disruption of GABAergic
inhibitory neurons (also known as interneurons) has the potential to perturb fundamental cortical functions, such
as accurate encoding of sensory information and higher-order cognition. One major challenge in exploring
GABAergic dysfunction is the diversity of inhibitory interneurons, which can be subdivided into distinct classes
with different physiology, synaptic targets, and molecular markers. In the cortex, the largest interneuron class is
comprised of fast-spiking basket cells that express parvalbumin (PV) and target the cell bodies of excitatory
neurons, providing rapid, powerful inhibition. Dysregulation of PV-interneurons has been suggested as a
candidate mechanism underlying autism, but little is known about the mechanistic contribution of PV-
interneurons to ASD-related deficits. Selective disruption of PV-interneuron function in the context of ASD in will
provide novel insight into specific GABAergic regulation and dysfunction in ASD.
 Genetic studies of ASD patients have identified Mef2c as a candidate gene. Small de novo deletions in
the Mef2c locus, as well as missense mutations, have been reported in several unrelated patients with autistic
features. Mef2c is an activity-dependent transcription that plays a role in synaptic function, and an
haploinsufficiency mouse model of Mef2c result in behavioral phenotypes characteristic of ASD. The
convergence of human studies, Mef2c function, and the ASD-like behaviors phenotypes present in the Mef2c
haploinsufficiency mouse model makes Mef2c an excellent candidate gene for addressing the molecular, cellular
and circuit dysfunctions underlying altered behavior in ASD. Mef2c is expressed in cortical excitatory neurons
and PV-interneurons, however thus far the cell type-specific role of Mef2c for PV-interneuron function and its
relation to ASDs remains unknown. Here, we will use combination of approaches that includes mouse genetics,
behavior, histology, synaptic physiology, in vivo electrophysiology, and transcriptomic analyses to test the
hypotheses that Mef2c signaling shapes PV-interneuron development, and that age-specific Mef2c-related
disruptions of PV-interneurons will impair different aspects of synaptic transmission and cortical activity, gaining
mechanistic insights into how impaired PV-interneuron dysfunction can contribute towards ASD symptoms.

## Key facts

- **NIH application ID:** 10475147
- **Project number:** 5F31HD101360-03
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Claire Ward
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475147

## Citation

> US National Institutes of Health, RePORTER application 10475147, Developmental Dysfunction of Parvalbumin Interneurons in Autism Spectrum Disorder (5F31HD101360-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475147. Licensed CC0.

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