# Autism Spectrum Disorders and Auditory System Deficits: Role of Neuronal and Immune System Dysfunction

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $641,726

## Abstract

ABSTRACT
Hearing impairment in children with autism spectrum disorders (ASDs) may contribute to core ASD symptoms
by interfering with language development and communication. The number of individuals with ASD or other
neurodevelopmental disorders is growing rapidly, thus studies are urgently needed to address how and to what
extent auditory system deficits are associated with ASD-like behaviors. Mounting evidence supports the
hypothesis that peripheral auditory system deficits reflective in auditory nerve dysfunction may contribute to the
pathophysiological changes observed at the cortical level (e.g., hyperacusis or other auditory processing
deficiencies). However, the lack of mechanistic studies using translational animal models of ASD with well-
characterized auditory functional impairments is a critical barrier to uncovering potential relationships and
causal links between structural and functional auditory deficits and ASD-related behaviors. Mutations or
deletions in the Myocyte-specific Enhancer Factor 2C (MEF2C) gene have been linked to ASD and other
neurodevelopmental disorders in humans. Our recent studies using a mouse model of human MEF2C
haploinsufficiency syndrome (MCHS) revealed that Mef2c deficiency leads to altered neural activity in the
cortex, increased microglial activation, and deficits in communication, social interaction, and other MCHS
symptoms that are characteristic of ASD. Using this mouse model, our studies also show (1) that Mef2c may
play a role in the development and function of spiral ganglion neurons of the auditory nerve and regulation of
cochlear macrophage activity, (2) an important association between Mef2c deficiency and auditory nerve
dysfunction, and (3) that Mef2c deficiency leads to cortical neural dysfunction in response to auditory stimuli.
Together these exciting data support the hypothesis that ASD risk-gene MEF2C deficiency in spiral ganglion
neurons and macrophages can lead to auditory nerve dysfunction and increased macrophage activation, which
in turn contributes to auditory cortical dysfunction and core symptoms of ASD. This multiple PI proposal will
test this novel hypothesis using a multidisciplinary approach. The proposed experiments will characterize
unique temporal and spatial expression patterns of Mef2c in both spiral ganglion neurons and cochlear
macrophages that are associated with auditory nerve development and maintenance (Aim 1), determine the
causal links between Mef2c deficiency-induced auditory nerve dysfunction and auditory cortical dysfunction,
and core symptoms of ASD (Aim 2), and test the extent to which inhibition of abnormal macrophage activation
ameliorates auditory nerve dysfunction, auditory cortical dysfunction, and core ASD symptoms (Aim 3). These
investigations will promote a greater understanding of the important role of immune cells and auditory system
deficits in ASD and possible other neurodevelopmental disorders and may reveal a neuro-immune-based
therapeutic strate...

## Key facts

- **NIH application ID:** 10977329
- **Project number:** 1R01DC021436-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Christopher W Cowan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $641,726
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977329

## Citation

> US National Institutes of Health, RePORTER application 10977329, Autism Spectrum Disorders and Auditory System Deficits: Role of Neuronal and Immune System Dysfunction (1R01DC021436-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10977329. Licensed CC0.

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