# Rescue of cortical inhibitory synapses following developmental hearing loss

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2021 · $63,948

## Abstract

PROJECT SUMMARY
Hearing loss (HL) is the most prevalent childhood sensory impairment, posing a risk for deficits in aural
communication. Moreover, these deficits can persevere even after normal audibility returns, suggesting that
developmental HL permanently impairs central synapse function which compromises auditory perception. In
fact, transient HL in gerbils induces perceptual deficits that are well-correlated with reduced inhibitory synaptic
strength in auditory cortex (ACx) (Caras & Sanes, 2015; Mowery et al. 2015, 2016). Furthermore, this deficit is
due to loss of both GABAA and GABAB receptor-mediated inhibition. Therefore, this proposal explores a causal
relationship between weakened inhibition and perceptual deficits. Our core hypothesis is that developmental
hearing loss induces a reduction of both postsynaptic GABAA- and GABAB receptor-mediated inhibition within
auditory cortex, thereby causing perceptual deficits. Three aims test predictions that emerge from this
hypothesis: Aim 1 tests the prediction that GABAA- and GABAB receptor-mediated inhibitory postsynaptic
potentials (IPSP) must each be rescued to regain normal inhibitory strength following HL. Gerbils will be reared
with transient bilateral HL (earplugs) from postnatal (P) days 11-23, and receive daily injections of a
GABAergic enhancer during this period. Animals will then be reared to adulthood (>P86) with normal hearing,
and an optogenetic approach will be used to assess GABAA and GABAB IPSPs in brain slices. To assess off-
target effects, both EPSPs and discharge properties will be measured. Comparisons will be made to vehicle-
treated HL and control animals. Aim 2 tests the prediction that HL-induced inhibitory weakening is intrinsic to
ACx pyramidal cells. Gerbils will be reared with HL from P11-23, and ACx layer 2/3 pyramidal cells will then be
transfected with genes that encode GABA receptor subunits or trafficking proteins, each obtained from the
newly available gerbil genome sequence. As in Aim 1, optogenetic assessment of IPSPs, EPSPs, and
discharge properties will be obtained from adult ACx. Aim 3 tests the prediction that perceptual deficits can be
restored by rescuing ACx synaptic inhibition. Gerbils will be reared with HL from P11-23 and receive either:
daily injections an effective GABA enhancer (Aim 1), or ACx transfection with an effective vector (Aim 2).
Animals will then be tested on an amplitude modulation (AM) detection task to obtain psychometric thresholds.
To determine whether perception correlates with inhibitory strength, an optogenetic assessment of IPSPs will
be obtained from the same animals. Innovations in this proposal are: (i) collaborations to sequence the gerbil
genome and to equip vectors with gerbil-specific genes, (ii) a high throughput assay of adult ACx synapse
function using optogenetics, and (iii) an emphasis on the role of GABAB receptors in developmental disorders.
Together, the significance of this proposal is to identify and remed...

## Key facts

- **NIH application ID:** 10359461
- **Project number:** 3R01DC011284-09S1
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Dan Harvey Sanes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $63,948
- **Award type:** 3
- **Project period:** 2010-12-10 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359461

## Citation

> US National Institutes of Health, RePORTER application 10359461, Rescue of cortical inhibitory synapses following developmental hearing loss (3R01DC011284-09S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10359461. Licensed CC0.

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