The hair cell synapse is the first step in the ascending auditory pathway. Disruption of this ribbon-type synapse can lead to severe hearing disorders. The goal of this proposal is to investigate how hair cell synaptic activity provides rapid signaling for long periods of time without fatigue. To maintain a continuous release of neurotransmitter the hair cell requires a large pool of synaptic vesicles that are readily releasable. However, the mechanisms that regulate synaptic vesicle endocytosis and the replenishment of vesicle pools in hair cells are poorly understood. We propose here to study fundamental aspects of synaptic transmission at inner hair cells (IHCs) in mouse cochlea and at auditory hair cells in the adult bullfrog amphibian papilla (AP). The AP preparation allows us to routinely access single hair cells and their afferent fibers for high-time-resolution patch-clamp electrophysiology and structure/function studies. We propose to use paired recordings of the hair cell and its connected afferent fiber to study multivesicular release and simultaneously to measure membrane capacitance changes from the hair cell to assay the exocytosis and endocytosis of synaptic vesicles. We will pursue three Specific Aims: First, we hypothesize that the fast and phasic component of release from hair cells requires high levels of ATP synthesis and hydrolysis, whereas the sustained component of release persists at a reduced rate even when ATP levels are very low. Accordingly, hair cells contain numerous mitochondria that are located near synaptic ribbons suggesting a need for a large amount of local ATP. Second, we will test the role of internal pH in controlling the rate of endocytosis in hair cells. Finally, we will study a transient block of the Ca2+ current in post-hearing mouse IHCs that is caused by the release of protons during multivesicular exocytosis. This transient block of the Ca2+ current constitutes a new method to study multivesicular release at IHC synapses and a new mechanism to explain the rapid spike adaption that is observed in vivo at the mammalian auditory nerve. Together these experiments will determine how pH changes affect endocytosis at hair cells and they will clarify the contributions of metabolic mechanisms that influence the auditory hair cell's ability to continuously release neurotransmitter.

Public Health Relevance

More than thirty million Americans suffer from significant hearing deficits which are mostly due to damage to hair cells or auditory nerve fibers in the inner ear. Our ability to treat this hearing loss, however, has been greatly hampered by a poor understanding of hair cell synapses. This proposal studies fundamental aspects of mature hair cell synaptic physiology and it will further our basic understanding of how to stimulate the auditory nerve fibers more physiologically, which may aid the design of future cochlea implants, which are devices that can partially restore hearing by directly stimulating the auditory nerve.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
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Oregon Health and Science University
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United States
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Johnson, Stuart L; Olt, Jennifer; Cho, Soyoun et al. (2017) The Coupling between Ca2+ Channels and the Exocytotic Ca2+ Sensor at Hair Cell Ribbon Synapses Varies Tonotopically along the Mature Cochlea. J Neurosci 37:2471-2484
Sebe, Joy Y; Cho, Soyoun; Sheets, Lavinia et al. (2017) Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse. J Neurosci 37:6162-6175
Rudolph, Stephanie; Tsai, Ming-Chi; von Gersdorff, Henrique et al. (2015) The ubiquitous nature of multivesicular release. Trends Neurosci 38:428-38
Cho, Soyoun; von Gersdorff, Henrique (2014) Proton-mediated block of Ca2+ channels during multivesicular release regulates short-term plasticity at an auditory hair cell synapse. J Neurosci 34:15877-87
Li, Geng-Lin; Cho, Soyoun; von Gersdorff, Henrique (2014) Phase-locking precision is enhanced by multiquantal release at an auditory hair cell ribbon synapse. Neuron 83:1404-17
Kim, Mean-Hwan; Li, Geng-Lin; von Gersdorff, Henrique (2013) Single Ca2+ channels and exocytosis at sensory synapses. J Physiol 591:3167-78
Kim, Jun Hee; von Gersdorff, Henrique (2012) Suppression of spikes during posttetanic hyperpolarization in auditory neurons: the role of temperature, I(h) currents, and the Na(+)-K(+)-ATPase pump. J Neurophysiol 108:1924-32
Cho, Soyoun; von Gersdorff, Henrique (2012) Ca(2+) influx and neurotransmitter release at ribbon synapses. Cell Calcium 52:208-16
Graydon, Cole W; Cho, Soyoun; Li, Geng-Lin et al. (2011) Sharp Ca²? nanodomains beneath the ribbon promote highly synchronous multivesicular release at hair cell synapses. J Neurosci 31:16637-50
Cho, Soyoun; Li, Geng-Lin; von Gersdorff, Henrique (2011) Recovery from short-term depression and facilitation is ultrafast and Ca2+ dependent at auditory hair cell synapses. J Neurosci 31:5682-92

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