""""""""Cholinergic inhibition of cochlear hair cells"""""""" is aimed at understanding the basic molecular mechanisms by which efferent neurons of the brainstem release acetylcholine (ACh) to inhibit hair cells and suppress cochlear sensitivity. This central feedback mechanism is particularly highly specialized in the mammalian cochlea where it is proposed to provide gain adjustment, improved signal to noise ratio, extended dynamic range and perhaps to protect from acoustic overstimulation. During development, temporary efferent contacts on inner hair cells are thought to modulate and shape spontaneous activity to help shape central connectivity. Finally, emerging evidence shows that efferent synaptic contacts return to aged or damaged inner hair cells, a process of great interest but presently unknown functional significance. The molecular mechanisms of inhibition may provide clues to these developmental and age-related changes. The hair cell's ACh receptor allows calcium entry that activates nearby potassium channels. This process is regulated by a near-membrane synaptic cistern. Ongoing work suggests that this cistern acts as a calcium sink during normal operation, but during periods of high activity executes calcium-induced calcium release that extends and prolongs cytoplasmic calcium signals. One consequence of prolonged calcium signaling is the activation of nitric oxide synthase to produce the diffusible messenger, nitric oxide (NO). NO causes retrograde facilitation of efferent transmitter release, thereby strengthening these contacts. Mechanisms that regulate efferent synaptic strength are of interest in the context of development, and the changes in synaptic organization that take place in aged or damaged cochleas. In addition to frank hair cell loss, it is clear that afferent denervation of inner hair ells is an important pathogenic change. The adventitious re-innervation of inner hair cells by efferent neurons may prevent afferent dendrites from re-claiming their territory on the hair cell. Understanding the determinants of efferent synapse formation provides tools for manipulating that process, perhaps to ameliorate one consequence of cochlear trauma.

Public Health Relevance

Hearing loss involves a variety of pathogenic mechanisms. Rearrangements of neuronal contacts can occur even without the frank death of sensory hair cells. The present proposal aims to understand better those synaptic rearrangements so as to identify potential therapeutic targets to ameliorate, or reverse, these forms of hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC001508-23
Application #
8756481
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
1992-09-30
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Zachary, Stephen Paul; Fuchs, Paul Albert (2015) Re-Emergent Inhibition of Cochlear Inner Hair Cells in a Mouse Model of Hearing Loss. J Neurosci 35:9701-6
Fuchs, Paul Albert (2015) How many proteins does it take to gate hair cell mechanotransduction? Proc Natl Acad Sci U S A 112:1254-5
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Fuchs, Paul Albert (2014) A 'calcium capacitor' shapes cholinergic inhibition of cochlear hair cells. J Physiol 592:3393-401
Im, Gi Jung; Moskowitz, Howard S; Lehar, Mohammed et al. (2014) Synaptic calcium regulation in hair cells of the chicken basilar papilla. J Neurosci 34:16688-97
Fuchs, Paul Albert; Lehar, Mohamed; Hiel, Hakim (2014) Ultrastructure of cisternal synapses on outer hair cells of the mouse cochlea. J Comp Neurol 522:717-29

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