""""""""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.
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.
|Wedemeyer, Carolina; Vattino, Lucas G; Moglie, Marcelo J et al. (2018) A Gain-of-Function Mutation in the ?9 Nicotinic Acetylcholine Receptor Alters Medial Olivocochlear Efferent Short-Term Synaptic Plasticity. J Neurosci 38:3939-3954|
|Boero, Luis E; Castagna, Valeria C; Di Guilmi, Mariano N et al. (2018) Enhancement of the Medial Olivocochlear System Prevents Hidden Hearing Loss. J Neurosci 38:7440-7451|
|Zachary, Stephen; Nowak, Nathaniel; Vyas, Pankhuri et al. (2018) Voltage-Gated Calcium Influx Modifies Cholinergic Inhibition of Inner Hair Cells in the Immature Rat Cochlea. J Neurosci 38:5677-5687|
|Moglie, Marcelo J; Fuchs, Paul A; Elgoyhen, Ana Belén et al. (2018) Compartmentalization of antagonistic Ca2+ signals in developing cochlear hair cells. Proc Natl Acad Sci U S A 115:E2095-E2104|
|Boffi, Juan Carlos; Marcovich, Irina; Gill-Thind, JasKiran K et al. (2017) Differential Contribution of Subunit Interfaces to ?9?10 Nicotinic Acetylcholine Receptor Function. Mol Pharmacol 91:250-262|
|Wu, Ping-Feng; Chuang, Chien; Su, Chin-Fang et al. (2016) High minimum inhibitory concentration of imipenem as a predictor of fatal outcome in patients with carbapenem non-susceptible Klebsiella pneumoniae. Sci Rep 6:32665|
|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|
|Fuchs, P A; Glowatzki, E (2015) Synaptic studies inform the functional diversity of cochlear afferents. Hear Res 330:18-25|
|Rohmann, Kevin N; Wersinger, Eric; Braude, Jeremy P et al. (2015) Activation of BK and SK channels by efferent synapses on outer hair cells in high-frequency regions of the rodent cochlea. J Neurosci 35:1821-30|
Showing the most recent 10 out of 49 publications