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.
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.
|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|
|Kaczmarek, Leonard K; Aldrich, Richard W; Chandy, K George et al. (2017) International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels. Pharmacol Rev 69:1-11|
|Kaczmarek, Leonard K; Zhang, Yalan (2017) Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance. Physiol Rev 97:1431-1468|
|Chambers, Anna R; Pilati, Nadia; Balaram, Pooja et al. (2017) Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage. Sci Rep 7:17496|
|Khare, Swati; Nick, Jerelyn A; Zhang, Yalan et al. (2017) A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. PLoS One 12:e0173565|
|Onorati, Marco; Li, Zhen; Liu, Fuchen et al. (2016) Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Rep 16:2576-2592|
|Zhang, Yalan; Kaczmarek, Leonard K (2016) Kv3.3 potassium channels and spinocerebellar ataxia. J Physiol 594:4677-84|
|Fleming, Matthew R; Brown, Maile R; Kronengold, Jack et al. (2016) Stimulation of Slack K(+) Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex. Cell Rep 16:2281-8|
|Zhang, Yalan; Zhang, Xiao-Feng; Fleming, Matthew R et al. (2016) Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating. Cell 165:434-448|
|Brown, Maile R; El-Hassar, Lynda; Zhang, Yalan et al. (2016) Physiological modulators of Kv3.1 channels adjust firing patterns of auditory brain stem neurons. J Neurophysiol 116:106-21|
Showing the most recent 10 out of 58 publications