"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)
Type
Research Project (R01)
Project #
2R01DC001508-23
Application #
8756481
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
Project End
Budget Start
Budget End
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
Fuchs, Paul Albert (2014) A 'calcium capacitor' shapes cholinergic inhibition of cochlear hair cells. J Physiol 592:3393-401
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
Kong, Jee-Hyun; Zachary, Stephen; Rohmann, Kevin N et al. (2013) Retrograde facilitation of efferent synapses on cochlear hair cells. J Assoc Res Otolaryngol 14:17-27
Wedemeyer, Carolina; Zorrilla de San Martin, Javier; Ballestero, Jimena et al. (2013) Activation of presynaptic GABA(B(1a,2)) receptors inhibits synaptic transmission at mammalian inhibitory cholinergic olivocochlear-hair cell synapses. J Neurosci 33:15477-87
Elgoyhen, Ana Belen; Katz, Eleonora (2012) The efferent medial olivocochlear-hair cell synapse. J Physiol Paris 106:47-56
Lipovsek, Marcela; Im, Gi Jung; Franchini, Lucia F et al. (2012) Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor. Proc Natl Acad Sci U S A 109:4308-13
Ballestero, Jimena; Zorrilla de San Martin, Javier; Goutman, Juan et al. (2011) Short-term synaptic plasticity regulates the level of olivocochlear inhibition to auditory hair cells. J Neurosci 31:14763-74
Elgoyhen, Ana Belen; Franchini, Lucia F (2011) Prestin and the cholinergic receptor of hair cells: positively-selected proteins in mammals. Hear Res 273:100-8
Wersinger, Eric; Fuchs, Paul Albert (2011) Modulation of hair cell efferents. Hear Res 279:1-12
Wersinger, Eric; McLean, Will J; Fuchs, Paul A et al. (2010) BK channels mediate cholinergic inhibition of high frequency cochlear hair cells. PLoS One 5:e13836

Showing the most recent 10 out of 34 publications