Our long-term goals are centered on understanding synaptic transmission and neurotransmitters in the cochlea. In this project period, we will focus on dynamic regulation of afferent transmission and its role in achieving some of the remarkable characteristics of auditory stimulus coding. The temporal precision and dynamic range encoded in auditory neurons is astonishing when one considers that this process is mediated by the hair cell releasing packets of neurotransmitter and that the entire input to the auditory nerve fiber is encoded in a single synapse. The achievement of these stimulus coding capabilities in a single synapse requires a number of specializations, not the least of which must be some formidable mechanisms to regulate synaptic strength over time. We will apply recent advances in understanding glutamatergic synapses in the CMS to examine dynamic regulation of auditory transmission.
First (aim 1), we will explore the hypothesis that the presence of glutamate (AMPA) receptors in the synaptic membrane of auditory neurons is dynamically regulated, and will focus on the roles of activation of NMDA and metabotropic glutamate receptors in this phenomenon. Work in our laboratory indicates robust regulation of AMPA receptors in auditory neurons.
Second (aim 2), we will examine the hypothesis that transmitter release may be regulated through activation of metabotropic glutamate receptors coupled to calcium-induced calcium release. Finally (aim 3), we will explore the biochemical implications for auditory transmission of the surprising recent finding that the major protein in the synaptic ribbon, an unusual structure associated with the afferent synapse on the hair cell, is a functional enzyme, an NAD dependent, D isomer specific 2 hydroxyacid dehydrogenase. Understanding how synaptic strength is regulated may aid in developing treatments for disorders in which these regulatory mechanism may be evoked, such as excitotoxic responses to trauma, tinnitus, and Meniere's syndrome. This work could provide a scientific basis for evaluating and modifying drug treatments for those problems. Last, but not least, because the demands on synaptic transmission for auditory coding far exceed those at any other synapse, it should not be surprising that several interesting facets of neurotransmission are highly developed in the cochlea. Examples include adaptations of the AMPA receptor for temporal precision and of transmitter release mechanisms for fine control of graded release. Mechanisms for dynamic and precise regulation of synaptic strength may be yet another instance in which basic biological machinery is highly adapted for auditory processing. If so, then analysis and understanding of these phenomena in auditory neurons could ultimately lead to insight useful in understanding CNS transmission.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
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Massachusetts Eye and Ear Infirmary
United States
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Kantardzhieva, Albena; Liberman, M Charles; Sewell, William F (2013) Quantitative analysis of ribbons, vesicles, and cisterns at the cat inner hair cell synapse: correlations with spontaneous rate. J Comp Neurol 521:3260-71
Peppi, Marcello; Landa, Melissa; Sewell, William F (2012) Cochlear kainate receptors. J Assoc Res Otolaryngol 13:199-208
Kantardzhieva, A; Peppi, M; Lane, W S et al. (2012) Protein composition of immunoprecipitated synaptic ribbons. J Proteome Res 11:1163-74
Peppi, Marcello; Kujawa, Sharon G; Sewell, William F (2011) A corticosteroid-responsive transcription factor, promyelocytic leukemia zinc finger protein, mediates protection of the cochlea from acoustic trauma. J Neurosci 31:735-41
Chen, Zhiqiang; Peppi, Marcello; Kujawa, Sharon G et al. (2009) Regulated expression of surface AMPA receptors reduces excitotoxicity in auditory neurons. J Neurophysiol 102:1152-9
Chen, Zhiqiang; Mikulec, Anthony A; McKenna, Michael J et al. (2006) A method for intracochlear drug delivery in the mouse. J Neurosci Methods 150:67-73
Sewell, W F; Mroz, E A; Evans, J E (2005) Extracts of retina and brain that excite afferent fibers innervating hair cells contain a compound related to hydroxyphenylglycine-N-carbamoyl. Synapse 58:129-40
Dawkins, Rosie; Keller, Sarah L; Sewell, William F (2005) Pharmacology of acetylcholine-mediated cell signaling in the lateral line organ following efferent stimulation. J Neurophysiol 93:2541-51
Chen, Zhiqiang; Kujawa, Sharon G; McKenna, Michael J et al. (2005) Inner ear drug delivery via a reciprocating perfusion system in the guinea pig. J Control Release 110:1-19
Dawkins, Rosie; Sewell, William F (2004) Afferent synaptic transmission in a hair cell organ: pharmacological and physiological analysis of the role of the extended refractory period. J Neurophysiol 92:1105-15

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