The Auditory Phenotype of Kv Channel Gene Mutations

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DESCRIPTION (provided by applicant): The long-term objective of the proposed work is to understand how the intrinsic electrical excitability of neurons in central auditory system contributes to auditory signal processing. The type and amount of voltage- gated potassium (Kv) channels expressed in the cell membrane determine the shape, probability and temporal patterning of action potentials and therefore principally determine a neuron's intrinsic electrical excitability. Detailed analyses of Kv channel biochemistry and biophysics indicate that two Kv channels, Kv3.1 and Kv1.3, exhibit properties that are particularly germane to the aims of this proposal. Kv1.3 and Kv3.1 have been observed to have significant - and often opposing - roles in regulating the neuronal response threshold, maximum sustained firing rate and maximum following rate. Alterations in these response features have clear implications for acoustic signal processing, which will be explored in depth through the combined use of neurophysiological and behavioral assays in Kv3.1 and Kv1.3 knockout mice. Aim 1 seeks to characterize the effects of Kv3.1 and Kv1.3 deletion at the level of the single unit within the inferior colliculus (IC). Neurophysiological selectivity for variations in sound frequency, temporal envelope properties, intensity and binaural interaction will be compared in awake Kv3.1 null, Kv1.3 null and wild-type mice. Aim 2 would relate variations in neurophysiological responses to commensurate shifts in hearing thresholds. These experiments will implement a conditioned avoidance protocol to measure detection and discrimination thresholds for variations in sound frequency, temporal structure and intensity. Through the combined application of genetic, neurophysiological and behavioral analyses, the proposed experiments would further our understanding of how the basic building blocks of excitability in the brain impact auditory processing and perception. Relevance: These experiments will further our understanding of the molecular determinants of brain function and behavior. By studying the effects of single gene deletions on the physiological response properties of single cells in the brain and the hearing abilities of animals actively engaged in listening tasks, the proposed experiments may allow us to frame the effects of genetic mutations in a more integrative context of auditory system function. Furthermore, the proposed experiments could shed additional light on the role of intrinsic neuronal excitability in the context of auditory information processing as well as pathological states such as audiogenic seizure.