# Mechanisms of hypersensitivity to sound-induced cochlear damage

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $589,359

## Abstract

Project Summary
All information about the acoustic environment is carried from the inner ear to the CNS by the afferent fibers of
the cochlear nerve. Rapidly gating AMPA glutamate receptors (AMPAR; GluA2, GluA3 and GluA4 subunits)
mediate synaptic transmission at the mature synapse between the inner hair cells (IHC) and the afferent fibers
of the cochlear nerve (IHC synapse). However, the contribution of each type of AMPAR subunit to overall
glutamatergic receptor function and afferent transmission/sensitivity in the cochlea is poorly understood.
Understanding this process is important because glutamate excitotoxicity through AMPAR has been implicated
in the pathogenesis of hearing loss caused by noise, ischemia and aging. Sex differences in the vulnerability to
hearing loss occur in humans. We therefore began investigating the contribution of AMPAR subunits to
transmission at the IHC synapse and whether there are sex-specific differences in AMPAR subunits that
contribute to sound-induced cochlear damage and hearing loss. Based on functional and ultrastructural
preliminary data, we now hypothesize that “GluA3 AMPAR subunits have a critical role in the sexually
dimorphic vulnerability to hearing loss”. To define mechanistically how GluA3 contributes to the structural and
molecular components of IHC synapses and to sex differences that underlie the hypersensitivity to sound-
induced cochlear damage, we will use a powerful combination of functional (ABRs, DPOAEs),
immunocytochemical (confocal microscopy), biochemical, qRT-PCR, and ultrastructural approaches to test the
following hypotheses. In Aim 1, we will determine whether GluA3 promotes the abundance of GluA2 at IHC
synapses. In Aim 2, we will determine whether GluA3 at IHC synapses protects mice from sound-induced
cochlear damage. Aim 3, based on published data and our preliminary findings, we propose the hypothesis
that in the absence of GluA3, ovarian hormones facilitate the hypersensitivity to sound-induced cochlear
damage, while androgens have protective effects. These proposed studies are the first to address the
important question of how changes in AMPAR subunit composition lead to sex differences in hearing loss.

## Key facts

- **NIH application ID:** 10200747
- **Project number:** 5R01DC013048-08
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Maria-Eulalia Rubio-Valero
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $589,359
- **Award type:** 5
- **Project period:** 2013-03-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200747

## Citation

> US National Institutes of Health, RePORTER application 10200747, Mechanisms of hypersensitivity to sound-induced cochlear damage (5R01DC013048-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200747. Licensed CC0.

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