Our objective is to understand the mechanisms of intercellular communication between neurons in the mammalian central nervous system. We focus on the roles played by postsynaptic membrane conductances in the transduction of chemically- mediated synaptic signals into spike trains. Our experiments will use isolated neocortical brain slices, dissociated adult neurons, intracellular recording, single electrode voltage clamp and patch clamp techniques. We will use voltage clamp, pharmacological blocking agents and a mathematical model to test hypotheses about the functions of five identified K+ currents. Our experiments have revealed that muscarine and norepinephrine decrease the same two K+ currents in neocortical cells, and the proposed studies are designed to further elucidate the mechanism whereby two apparently different second messenger systems mediate a similar physiological action. We will study the action of the neuropeptide modulators vasoactive intestinal polypeptide and cholecystokinin octapeptide sulfate. By isolating the dendrites from the soma and using dissociated adult neurons, we will identify the location and properties of Ca2+ currents in neocortical cells. These studies will answer fundamental questions about the mechanisms involved in synaptic communication between neurons. The specific neurons studied are those giving rise to the primary motor output of cerebral cortex. The results of these experiments will serve as a foundation for formulating hypotheses about epileptic mechanisms in neocortex and will contribute to our understanding of diseases such as amyotrophic lateral sclerosis and Alzheimer's disease.
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