Neurons in auditory brainstem pathways are capable of firing at very high rates with extraordinarily high temporal precision, allowing them to encode features of sound stimuli such as frequency, intensity and localization in space. Our ongoing research program in K+ channels over the past twenty years has cloned and identified many of the channels that determine the intrinsic electrical properties of neurons, and demonstrated that phosphorylation of such channels alters neuronal excitability. These channels include the Shaw-family Kv3.1b and Kv3.3 channels and the two-pore family TWIK channel, which are found at high levels in the presynaptic terminals of cochlear nucleus neurons and their postsynaptic targets, neurons of the medial nucleus of the trapezoid body. Evidence indicates that the intrinsic electrical properties of these neurons undergo rapid modification in response to changes in the auditory environment or to brief high frequency stimulation. We plan to determine the mechanism of these changes in excitability and to determine how they adapt the cell bodies and the presynaptic terminals to different frequencies of stimulation. The role of phosphorylation/dephosphorylation of the potassium channel subunits will be assessed using phospho-specific antibodies for immunocytochemistry and by direct electrophysiological measurements in mice in which one or more of the subunits have been deleted by homologous recombination. We will also test the hypothesis that the leakage potassium current in these neurons, which determines the membrane time constant, and therefore plays a central role in accuracy of timing, is regulated by changes in the sumoylation or phosphorylation state of the TWIK channel. An understanding of how rapid changes in the function of ion channels adapt the nervous system to different sensory environments may lead to therapies for a variety of hearing disorders including tinnitus, age-related hearing loss and audiogenic seizures.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
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Biophysics of Synapses, Channels, and Transporters Study Section (BSCT)
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Cyr, Janet
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Yale University
Schools of Medicine
New Haven
United States
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Gribkoff, Valentin K; Kaczmarek, Leonard K (2017) The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. Neuropharmacology 120:11-19
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