Mechanosensory hair cells in the vestibular system transduce information about head position and movement into neuronal signals.
The aim of this application is to elucidate the molecular mechanisms underlying synaptic transmission from vestibular hair cells to afferent fibers. The hair cells afferent synapse exhibits anatomical (synaptic bodies or ribbons) and functional (responding to graded depolarizations) specializations that distinguish them from other synapses in the nervous system. We here propose to investigate which proteins and protein-interactions important at conventional synapses are important for hair cell synaptic transmission. Furthermore, vestibular physiology lacks an understanding of the functional difference between type I and type II hair cells. Type I hair cells, found only in amniotes, are engulfed by the afferent nerve, suggesting differences in synaptic physiology. The proposed experiments are therefore further aimed at understanding the molecular and functional difference in neurotransmitter release between vestibular type I and type II hair cells. These experiments will further our molecular and biophysical understanding of the first synapse in the vestibular and auditory system. Hair cells release neurotransmitter from the basolateral end of the cell body, offering relatively easy access to synaptic areas for the introduction of toxins and peptides to acutely perturb protein function. Exocytosis will be monitored directly by measuring the increase in cell membrane area that occurs when vesicles fuse with the plasma membrane.
Specific Aim 1 tests the hypothesis that exocytosis is regulated by a specific subset of SNARE proteins.
Specific Aim 2 addresses whether vesicle recycling is limiting for exocytosis.
In Specific Aim 3 the hypothesis is tested that glutamate acts in a positive feedback loop to enhance release especially in type I hair cells. A detailed understanding of the proteins and mechanisms of release at this initial sensory synapse aid in identifying novel therapeutic approaches targeting vestibular dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007678-03
Application #
7237323
Study Section
Special Emphasis Panel (ZDC1-SRB-W (44))
Program Officer
Freeman, Nancy
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$219,741
Indirect Cost
Name
University of California Los Angeles
Department
Neurosciences
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Schweizer, Felix E; Savin, David; Luu, Cindy et al. (2009) Distribution of high-conductance calcium-activated potassium channels in rat vestibular epithelia. J Comp Neurol 517:134-45
Cruz-Martin, Alberto; Schweizer, Felix E (2008) Imbalance between excitation and inhibition among synaptic connections of CA3 pyramidal neurons in cultured hippocampal slices. Eur J Neurosci 27:1353-63