A Gain-of-Function Mutation in the alpha9 Nicotinic Acetylcholine Receptor Alters Medial Olivocochlear Efferent Short-Term Synaptic Plasticity

Wedemeyer, C., Vattino, L. G., Moglie, M. J., Ballestero, J., Maison, S. F., Di Guilmi, M. N., Taranda, J., Liberman, M. C., Fuchs, P. A., Katz, E., Elgoyhen, A. B. (April 2018) A Gain-of-Function Mutation in the alpha9 Nicotinic Acetylcholine Receptor Alters Medial Olivocochlear Efferent Short-Term Synaptic Plasticity. J Neurosci, 38 (16). pp. 3939-3954. ISSN 0270-6474

URL: https://www.ncbi.nlm.nih.gov/pubmed/29572431
DOI: 10.1523/jneurosci.2528-17.2018


Gain control of the auditory system operates at multiple levels. Cholinergic medial olivocochlear (MOC) fibers originate in the brainstem and make synaptic contacts at the base of the outer hair cells (OHCs), the final targets of several feedback loops from the periphery and higher-processing centers. Efferent activation inhibits OHC active amplification within the mammalian cochlea, through the activation of a calcium-permeable alpha9alpha10 ionotropic cholinergic nicotinic receptor (nAChR), functionally coupled to calcium activated SK2 potassium channels. Correct operation of this feedback requires careful matching of acoustic input with the strength of cochlear inhibition (Galambos, 1956; Wiederhold and Kiang, 1970; Gifford and Guinan, 1987), which is driven by the rate of MOC activity and short-term facilitation at the MOC-OHC synapse (Ballestero et al., 2011; Katz and Elgoyhen, 2014). The present work shows (in mice of either sex) that a mutation in the alpha9alpha10 nAChR with increased duration of channel gating (Taranda et al., 2009) greatly elongates hair cell-evoked IPSCs and Ca(2+) signals. Interestingly, MOC-OHC synapses of L9'T mice presented reduced quantum content and increased presynaptic facilitation. These phenotypic changes lead to enhanced and sustained synaptic responses and OHC hyperpolarization upon high-frequency stimulation of MOC terminals. At the cochlear physiology level these changes were matched by a longer time course of efferent MOC suppression. This indicates that the properties of the MOC-OHC synapse directly determine the efficacy of the MOC feedback to the cochlea being a main player in the "gain control" of the auditory periphery.SIGNIFICANCE STATEMENT Plasticity can involve reciprocal signaling across chemical synapses. An opportunity to study this phenomenon occurs in the mammalian cochlea whose sensitivity is regulated by efferent olivocochlear neurons. These release acetylcholine to inhibit sensory hair cells. A point mutation in the hair cell's acetylcholine receptor that leads to increased gating of the receptor greatly elongates IPSCs. Interestingly, efferent terminals from mutant mice present a reduced resting release probability. However, upon high-frequency stimulation transmitter release facilitates strongly to produce stronger and far longer-lasting inhibition of cochlear function. Thus, central neuronal feedback on cochlear hair cells provides an opportunity to define plasticity mechanisms in cholinergic synapses other than the highly studied neuromuscular junction.

Item Type: Paper
Uncontrolled Keywords: cochlea efferent inhibition hair cells synaptic plasticity alpha9alpha10 nAChR
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > synaptic plasticity
CSHL Authors:
Communities: CSHL labs > Osten lab
Depositing User: Matt Covey
Date: 18 April 2018
Date Deposited: 22 May 2018 20:54
Last Modified: 21 Dec 2023 15:27
PMCID: PMC5907056
Related URLs:
URI: https://repository.cshl.edu/id/eprint/36570

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