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.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
El-Hassar, Lynda; Simen, Arthur A; Duque, Alvaro et al. (2014) Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels. Biol Psychiatry 76:476-85
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
Markham, Michael R; Kaczmarek, Leonard K; Zakon, Harold H (2013) A sodium-activated potassium channel supports high-frequency firing and reduces energetic costs during rapid modulations of action potential amplitude. J Neurophysiol 109:1713-23
Cotella, Diego; Hernandez-Enriquez, Berenice; Duan, Zhibing et al. (2013) An evolutionarily conserved mode of modulation of Shaw-like K? channels. FASEB J 27:1381-93
Kaczmarek, Leonard K (2012) Gradients and modulation of K(+) channels optimize temporal accuracy in networks of auditory neurons. PLoS Comput Biol 8:e1002424
Brown, Maile R; Kaczmarek, Leonard K (2011) Potassium channel modulation and auditory processing. Hear Res 279:32-42
Chen, Ying-Bei; Aon, Miguel A; Hsu, Yi-Te et al. (2011) Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J Cell Biol 195:263-76
Gazula, Valeswara-Rao; Strumbos, John G; Mei, Xiaofeng et al. (2010) Localization of Kv1.3 channels in presynaptic terminals of brainstem auditory neurons. J Comp Neurol 518:3205-20
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

Showing the most recent 10 out of 44 publications