) A major challenge confronting neurobiology is to define how specific voltage-gated potassium (Kv) channel genes influence the timing, duration and frequency of the neuronal signals that encode and transmit information. Neurons in the auditory system have the unique advantages of relatively simple circuitry, well defined functional roles (involving precise signal fidelity) and strong expression of Kv currents. The goal of this proposal is to examine the functional roles of Kv channel genes in three types of auditory neuron-bushy neurons and octopus cells of the cochlear nucleus. and neurons of the medial nucleus of the trapezoid body -each performing related but distinct information processing tasks. Using molecular and irnmunocytochemical techniques, the applicant will determine the complement of Kv channel subunits expressed in these neurons and examine their subcellular localizations. Using electrophysiological techniques, the applicant will characterize Kv currents in these auditory neurons in brainstem slices from wildtype mice and from hearing impaired mice that lack the Kv1.1 channel subunit gene (i.e. Kvl.l knockout mice). These data should reveal rules governing Kv channel assembly and localization in parts of the neuron specialized for either encoding or transmission of information, and elucidate specialized roles in auditory information processing for different subunits, or subsets of subunits within a subfamily. Our thorough characterization of the functional role of Kv channels at the cellular level will also help to explain at the organismal level the hearing loss, movement abnormalities and seizures observed in Kvl.1 knockout mice. Using both anatomical and electrophysiological data, the applicant will develop computer models to assess the relevance of Kv channels/currents in auditory information processing. The model will be used to predict the effects of removing other Kv genes strongly expressed in auditory neurons, such as Kv 1.2 for which the applicant's predictions will be tested directly by examining Kvl.2 knockout mice. Episodic ataxia myokymia is caused by mutations in the Kvl.1 (KCNA1) gene in humans. Clinical reports on these patients often include tinnitus, vertigo and sometimes profound hearing loss. The proposed studies and models based on the Kvl.1 knockout mouse mutants should also be informative regarding the neuronal dysfunction that underlies this human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003805-05
Application #
6618084
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Freeman, Nancy
Project Start
1999-08-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2005-07-31
Support Year
5
Fiscal Year
2003
Total Cost
$313,729
Indirect Cost
Name
University of Washington
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Brew, Helen M; Gittelman, Joshua X; Silverstein, Robert S et al. (2007) Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J Neurophysiol 98:1501-25
Gittelman, Joshua X; Tempel, Bruce L (2006) Kv1.1-containing channels are critical for temporal precision during spike initiation. J Neurophysiol 96:1203-14
Brew, Helen M; Forsythe, Ian D (2005) Systematic variation of potassium current amplitudes across the tonotopic axis of the rat medial nucleus of the trapezoid body. Hear Res 206:116-32
Brew, Helen M; Hallows, Janice L; Tempel, Bruce L (2003) Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1. J Physiol 548:1-20
Lopantsev, Valeri; Tempel, Bruce L; Schwartzkroin, Philip A (2003) Hyperexcitability of CA3 pyramidal cells in mice lacking the potassium channel subunit Kv1.1. Epilepsia 44:1506-12
Jiang, X; Zhang, Y H; Clark, J D et al. (2003) Prostaglandin E2 inhibits the potassium current in sensory neurons from hyperalgesic Kv1.1 knockout mice. Neuroscience 119:65-72
Kopp-Scheinpflug, Cornelia; Fuchs, Katja; Lippe, William R et al. (2003) Decreased temporal precision of auditory signaling in Kcna1-null mice: an electrophysiological study in vivo. J Neurosci 23:9199-207
van Brederode, J F; Rho, J M; Cerne, R et al. (2001) Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice. Neuroscience 103:921-9