This proposal seeks to investigate mechanisms of synaptic transmission at the inner hair cell (IHC) afferent synapse in the mammalian cochlea. In the inner ear, sound signals are converted into hair cell receptor potentials, and subsequently are translated at the afferent synapse into firing rates in auditory nerve fibers. Coding of sound critically depends on the diverse firing properties of auditory nerve fibers. Important features of auditory nerve fibers are their spontaneous firing rates, their thresholds of activation and their `rate level functions', describing the changes in firing rates in response to different sound pressure levels. Three main `sites'in cochlear transmission have been suggested to determine auditory nerve fiber properties: 1) basilar membrane mechanics;2) IHC receptor potential;3) IHC afferent synaptic transmission. Convincing arguments have been made that auditory nerve fibers with distinct properties (low versus high spontaneous rates;high versus low thresholds of activation) innervate the same IHCs. However, all 10-20 afferent fibers contacting one IHC `sense'the same receptor potential and therefore it is likely that differences in afferent fiber properties must arise at single synapses.
The aim of this study is to ask which properties of auditory nerve fibers arise at the IHC afferent synapse, and how pre- and/or postsynaptic components specifically determine these properties. Excised cochlear tissue from 2-4 week old rodents will be used to perform simultaneous whole cell recordings from IHCs and afferent fiber terminals directly where they contact the IHCs. The transfer function at the IHC afferent synapse will be measured directly by controlling the IHC membrane potential and monitoring postsynaptic activity in the afferent terminal. Extracellular recordings will be used to monitor the rate of action potentials at the afferent terminal. Key to this approach is that it allows recordings after hearing onset, when the diverse properties of auditory nerve fibers have developed. Afferent fiber spontaneous rates, thresholds and transfer functions will be determined and afferent fiber adaptation will be measured. Simultaneous recordings from pairs of afferent fibers will provide a direct test of whether fibers with different properties do innervate a single IHC. Hypotheses based on in vivo experiments that have suggested specific loci as the origin for specific auditory nerve fiber properties will be reevaluated. The specific pre-or postsynaptic mechanisms responsible for specific firing patterns will be further investigated. A better understanding of the mechanisms that underlie the generation of diverse auditory nerve fiber firing properties will provide the basis for an improvement in cochlear implant design. The studies outlined in this proposal seek to understand the mechanisms that underlie synaptic transmission at the first synapse in the auditory pathway, the synapse between hair cells and auditory nerve fibers. The conversion of the hair cell receptor potential into a firing rate in the auditory nerve fibers is an important step in coding the sound signal for transmission to the brain. Our results will support studies that aim to model how auditory nerve activity is generated. These approaches can provide a future basis for better cochlear implant design.

Public Health Relevance

The studies outlined in this proposal seek to understand the mechanisms that underlie synaptic transmission at the first synapse in the auditory pathway, the synapse between hair cells and auditory nerve fibers. The conversion of the hair cell receptor potential into a firing rate in the auditory nerve fibers is an important step in coding the sound signal for transmission to the brain. Our results will support studies that aim to model how auditory nerve activity is generated. These approaches can provide a future basis for better cochlear implant design.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006476-10
Application #
8386905
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2004-01-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
10
Fiscal Year
2013
Total Cost
$317,274
Indirect Cost
$123,814
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Wu, Jingjing Sherry; Young, Eric D; Glowatzki, Elisabeth (2016) Maturation of Spontaneous Firing Properties after Hearing Onset in Rat Auditory Nerve Fibers: Spontaneous Rates, Refractoriness, and Interfiber Correlations. J Neurosci 36:10584-10597
Vyas, Pankhuri; Wu, Jingjing Sherry; Zimmerman, Amanda et al. (2016) Tyrosine Hydroxylase Expression in Type II Cochlear Afferents in Mice. J Assoc Res Otolaryngol :
Roux, Isabelle; Wu, Jingjing Sherry; McIntosh, J Michael et al. (2016) Assessment of the expression and role of the α1-nAChR subunit in efferent cholinergic function during the development of the mammalian cochlea. J Neurophysiol 116:479-92
Martinez-Monedero, Rodrigo; Liu, Chang; Weisz, Catherine et al. (2016) GluA2-Containing AMPA Receptors Distinguish Ribbon-Associated from Ribbonless Afferent Contacts on Rat Cochlear Hair Cells. eNeuro 3:
Fuchs, P A; Glowatzki, E (2015) Synaptic studies inform the functional diversity of cochlear afferents. Hear Res 330:18-25
Sadeghi, Soroush G; Pyott, Sonja J; Yu, Zhou et al. (2014) Glutamatergic signaling at the vestibular hair cell calyx synapse. J Neurosci 34:14536-50
Korrapati, Soumya; Roux, Isabelle; Glowatzki, Elisabeth et al. (2013) Notch signaling limits supporting cell plasticity in the hair cell-damaged early postnatal murine cochlea. PLoS One 8:e73276
Weisz, Catherine J C; Lehar, Mohamed; Hiel, Hakim et al. (2012) Synaptic transfer from outer hair cells to type II afferent fibers in the rat cochlea. J Neurosci 32:9528-36
Goutman, Juan D; Glowatzki, Elisabeth (2011) Short-term facilitation modulates size and timing of the synaptic response at the inner hair cell ribbon synapse. J Neurosci 31:7974-81
Grant, Lisa; Yi, Eunyoung; Goutman, Juan D et al. (2011) Postsynaptic recordings at afferent dendrites contacting cochlear inner hair cells: monitoring multivesicular release at a ribbon synapse. J Vis Exp :

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