The long tend goal of this project is to contribute to the understanding of the role of K+ channel diversity in the central nervous system (CNS). K+ channels are key regulators of neuronal excitability. They underlie many of the differences in electrophysiological properties that characterize specific neurons, contributing to the complexity of neuronal information coding and integration. It is hypothesized that their diversity provides signaling specificity to neuronal circuits and to the actions of neurotransmitters and neuropeptides. Mutations in genes encoding K+ channels have been found to cause human disease. The focus of this application is the thalamocortical (TC) system. The thalamus functions as a gate between the information received from the outside world and the generation of consciousness in the cerebral cortex. To reach the neocortex, sensory information must be first processed by thalamic relay neurons. Excitatory and inhibitory circuits in flee cortex process this information to create associations, produce an image of the sensory input and initiate proper responses. The emphasis of these studies is on Kv3.2, a gene encoding subunits of voltage-gated K+ channels, which, so far, have only been detected in the CNS. The overwhelming majority of Kv3.2 mRNAs are produced by thalamic relay neurons and the protein products are localized predominantly in the terminal fields of the axons of these cells, the TC projections. The TC synapse is flee last possible station where access to the cortex could be modulated. Modulations of TC communication mediate the admittance of information to the neocortex during different behavioral states and it is hypothesized that Kv3.2 K+ channels are key modulators of flee activity of TC projections. Kv3.2 proteins are also prominent in GABAergic cortical interneurons that play central roles in the processing of cortical information, including inhibition and synchronization of cortical circuits, the reorganization of representation maps, the generation of cortical rhythms, and in the pathogenesis of seizures. Mice deficient in the Kv3.2 gene have defects supporting the hypothesis that Kv3.2 channels play special roles in neuronal function. The mice have seizures, apparent deficits in the control of sleep behavior and alterations in cortical rhythms, including irregularities in slow sleep rhythms. Evoked potential studies suggest that TC communication is impaired. The Research Plan is focused on flee analysis of the cellular defects produced by flee lack of Kv3 .2 channels in transgenic mice, together with other pharmacological, molecular and histological tools previously developed, to understand the special roles of these channels in neuronal excitability. Whole cell recording of thalamocortical synaptic transmission will explore the roles of the channels in TC communication. Whole cell methods will be used as well to investigate the function of Kv3 .2 channels on the firing properties and synaptic transmission of neocortical GABAergic interneurons The modulation of TC transmission and cortical inhibitory function by protein kinases shown to modulate Kv3.2 channels in vitro will also be investigated.
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