# ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $325,125

## Abstract

SUMMARY
 The long-term goal of this project is to investigate mechanisms underlying noise-induced cochlear
synaptopathy and hidden hearing loss. Noise is a common risk factor for hearing loss. Recent studies
have demonstrated that even a single episode of noise overexposure induces transient hearing loss,
i.e., temporal threshold shift (TTS), noise-exposed animals could have no hair cell loss but have
extensive spiral ganglion neuron (SG) and synapse degeneration. In particular, low spontaneous rate
(LSR) auditory nerves and their synaptic connections with inner hair cells are preferentially lost. The
noise-exposed animals and humans demonstrate normal hearing threshold and sensitivity (i.e.,
hidden hearing loss) in the early stage but will eventually exhibit other hearing disorders and hearing
loss. Currently, the underlying mechanism for such cochlear synaptopathy remains unclear.
 Noise stimulates hair cell and neuron over-activation and increases K+ efflux that leads to
increasing extracellular K+ concentration. It is well-established that high extracellular K+ can induce
toxicity leading to second cell death in the brain following injury and stroke. We hypothesize that
high, excess extracellular K+ following noise exposure can also cause SG synapse and neuron
degeneration in the cochlea. We previously found that ATP purinergic P2X receptors in the cochlea
are required for sinking K+ to re-enter into cells. A recent study also demonstrated that P2X2
receptors are necessary for the development of TTS. In addition, we found that P2X2 mutation can
increase susceptibility to noise and induce hearing loss. These studies indicate that P2X receptors
may have a critical role in noise-induced cochlear synaptopathy and hidden hearing loss. In this
project, we will first test whether high extracellular K+ can cause SG synapse and neuron
degeneration (Specific Aim 1, SA1). Then, we will identify and characterize P2X receptor expression
in SG neurons, including LSR and HSR (high spontaneous rate) fiber synaptic endings, and test
whether P2X receptors can mediate K+-sinking in the SG neurons. In SA3, we will test whether
deficiency of P2X receptors can induce and exacerbate cochlear synaptopathy and hearing loss
following noise exposure and high-K+ challenge. Completion of these studies will directly reveal the
molecular mechanism underlying noise-induced cochlear synaptic degeneration and hidden hearing
loss. These novel studies will also open a new therapeutic avenue for targeting noise-induced hearing
loss and cochlear synaptopathy.

## Key facts

- **NIH application ID:** 9854924
- **Project number:** 5R01DC017025-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Hong-Bo Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,125
- **Award type:** 5
- **Project period:** 2018-03-22 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854924

## Citation

> US National Institutes of Health, RePORTER application 9854924, ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss (5R01DC017025-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854924. Licensed CC0.

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