Auditory brainstem neurons fire at very high rates with extraordinarily high temporal precision, allowing them to encode specific features of sound stimuli. Unexpectedly, it has been found that the levels and characteristics of potassium channels in these neurons are rapidly modified by the auditory environment. We plan to determine the mechanisms of this use-dependent plasticity for two classes of K+ channels, i) voltage-dependent Kv3.1b channels and ii) Na+-activated K+ channels (KNa channels) encoded by the Slack and Slick genes. The function of Kv3.1b channels is to allow neurons to fire at high frequencies. We plan to determine whether sound- induced increases in Kv3.1b protein levels result in higher Kv3.1b currents in the plasma membrane and enhance the ability of MNTB neurons to fire at higher rates. We also plan to test the hypothesis that KNa current amplitude is regulated by sound-induced changes in phosphorylation state to enhance the temporal accuracy of these neurons at high rates of stimulation. For both Kv3.1b and KNa channels we will determine whether the activity-dependent increases in current are regulated by the Fragile X Mental Retardation Protein (FMRP), a repressor of protein translation that binds Kv3.1 mRNA and that modulates KNa channels by direct protein- protein interactions. An understanding of how the excitability of auditory neurons is regulated by physiological stimuli is likely to lead to novel pharmacological treatments for disorders of auditory function including tinnitus, age-related hearing loss and audiogenic seizures, as well as Fragile X syndrome and other disorders of excitability.

Public Health Relevance

Recent evidence has shown that the excitability of auditory neurons within the brain is rapidly modified by changes in the ambient acoustic environment. The experiments in this proposal will determine the biochemical and biological mechanisms that adjust the properties of ion channels in these neurons, allowing them to maintain high accuracy in noisy environments. This information will be used to determine which classes of pharmacological agents can be used for the treatment of disorders of auditory function including tinnitus, age- related hearing loss and audiogenic seizures, as well as Fragile X syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC001919-21
Application #
8444258
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
1993-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
21
Fiscal Year
2013
Total Cost
$335,953
Indirect Cost
$134,078
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Lee, Amy; Fakler, Bernd; Kaczmarek, Leonard K et al. (2014) More than a pore: ion channel signaling complexes. J Neurosci 34:15159-69
Duque, Alvaro; Gazula, Valeswara-Rao; Kaczmarek, Leonard K (2013) Expression of Kv1.3 potassium channels regulates density of cortical interneurons. Dev Neurobiol 73:841-55
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Strumbos, John G; Brown, Maile R; Kronengold, Jack et al. (2010) Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b. J Neurosci 30:10263-71

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