In the vestibular system, as in the auditory and visual systems, stimuli are transduced and neural signals processed prior to transmission to the brain. Our research and that of others has clearly shown that the afferent responses from the semicircular canal deviate from canal biomechanics, and has implicated signal processing by the hair cell-primary afferent synapse in shaping the afferent response. Our overarching hypothesis is that the spatial distribution of an ensemble of transmitter and receptor phenotypes on hair cells and the afferent terminal arbors form processing entities that transform hair cell receptor potentials into the frequency code seen in the nerve discharge. The goal of the proposed research is to measure and quantify the contributions of these entities to the adaptation and frequency-dependent responses of vestibular semicircular canal afferents. We have demonstrated that there are three hair cell transmitter phenotypes: GABAergic, glutamatergic and cells that express both transmitters. We propose that specific combinations of hair cells and afferent terminals operating in feed-forward and feedback configurations dictate the transformation of canal biomechanical responses into the neural codes of individual primary afferent fibers. This proposal focuses on four categories of synaptic and/or extrasynaptic factors putatively involved in signal processing: (1) hair cell transmitter phenotype(s) impinging on a given ending, including the possibility of a diversity of hair cell transmitter phenotypes and post-synaptic receptor distributions interacting at a given terminal, (2) potential feedback between the calyx and hair cell, including feedback from hair cell-released transmitter to the hair cell itself, (3) the rate of transmitter release and subsequent synaptic current dynamics, governed by pre- and post-synaptic ionic currents present at a particular synapse, and (4) the integrative properties of the afferent dendrite. Understanding the complexity of the signal processing performed by afferent terminals is a necessary step toward developing treatments for vestibular disorders. Basic science adds information that is important in understanding normal and abnormal function. Once the precise mechanisms involved in shaping afferent dynamics are more thoroughly understood, appropriate and specific pharmacological agents may be developed to reduce abnormal bursts of afferent neural activity, thereby mitigating the severity of vertiginous symptoms in disorders such as M?ni?re's syndrome.

Public Health Relevance

The inner ear contains the organs of hearing, balance and equilibrium. We study synaptic communication by chemical transmitter between hair cells (the primary mechanical sensors) and their innervated nerve fibers. Results from these investigations are expected to support the development of targeted therapies for peripheral vestibular disorders such as M?ni?re's syndrome and benign paroxysmal positional vertigo.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC008142-04
Application #
8247709
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Cyr, Janet
Project Start
2009-04-03
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$449,290
Indirect Cost
$103,032
Name
Marine Biological Laboratory
Department
Type
DUNS #
001933779
City
Woods Hole
State
MA
Country
United States
Zip Code
02543
Highstein, Stephen M; Holstein, Gay R; Mann, Mary Anne et al. (2014) Evidence that protons act as neurotransmitters at vestibular hair cell-calyx afferent synapses. Proc Natl Acad Sci U S A 111:5421-6