# Contribution of Macrophages and Fractalkine Towards Degeneration and Repair of Cochlear Synapses

> **NIH NIH P20** · CREIGHTON UNIVERSITY · 2021 · $255,535

## Abstract

PROJECT SUMMARY/ABSTRACT
Noise trauma can primarily damage the synaptic connections between the inner hair cells and the peripheral
axons of the spiral ganglion neurons. Noise-induced synaptopathy is attributed to glutamate excitotoxicity and
leads to gradual axonal degeneration and ultimately death of the spiral ganglion neurons. The consequences
of loss of synapses and neurons include auditory perceptual dysfunctions leading to difficulty in speech
recognition and listening in noisy environments. This type of auditory dysfunction is known as “hidden hearing
loss” because it is not readily diagnosed through standard hearing tests. Moreover, absence of spiral
ganglion neurons limits the performance of primary therapies for hearing loss such as cochlear implants and
future hair cell regeneration strategies. Currently, there are no approved drugs that promote neuron survival
or elicit regeneration of lost auditory nerves and replenish their synaptic connections with surviving hair cells.
Therefore, it is of great interest to understand the mechanisms for synaptic and neuron degeneration and
regeneration for the development of better ototherapeutics. We recently demonstrated that synaptopathic noise
trauma is sufficient to recruit macrophages (innate-immune cells) towards the damaged inner hair cell-synaptic
region. While the damaged synapses can undergo spontaneous repair however, disruption of fractalkine
signaling (by genetic deletion of fractalkine (FKN) receptor CX3CR1 on macrophages) impairs such
spontaneous synaptic repair and increases spiral ganglion neuron loss after trauma. These data imply that
intact fractalkine signaling is necessary for synaptic repair and neuron survival in the damaged cochlea. Here,
we propose to investigate the effect of activation of fractalkine signaling on prevention and repair of loss
of synapses and neuron survival following cochlear trauma. Aim 1 will determine whether FKN treatment
repairs damaged synapses after noise trauma or excitotoxic insult in mammalian mouse cochlea.
Specifically, FKN peptide will be injected either (transtympanically) after synaptopathic noise trauma in vivo
or after glutamate- induced excitotoxicity in cochlear explants. The precise contribution of FKN membrane or
soluble isoforms towards synaptic repair will be examined. Aim 2 will determine whether FKN treatment
reduces degeneration of synapses following noise trauma or glutamate excitotoxicity. We will treat with FKN
membrane or soluble isoforms prior to glutamate treatment in ex vivo cochlear explants or prior to noise trauma
in vivo (transtympanically). In Aim 3, we will eliminate cochlear macrophages and examine the influence of
this intervention on the degree of synaptic degeneration and repair after synaptopathic noise trauma. For
each aim, auditory function along with morphometric analyses of hair cell, macrophage, synapse and spiral
ganglion neuron counts will be performed. Together, the study design will aid in investigat...

## Key facts

- **NIH application ID:** 10090991
- **Project number:** 1P20GM139762-01
- **Recipient organization:** CREIGHTON UNIVERSITY
- **Principal Investigator:** Tejbeer Kaur
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $255,535
- **Award type:** 1
- **Project period:** 2021-03-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090991

## Citation

> US National Institutes of Health, RePORTER application 10090991, Contribution of Macrophages and Fractalkine Towards Degeneration and Repair of Cochlear Synapses (1P20GM139762-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10090991. Licensed CC0.

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