The excitatory amino acid (EAA), glutamate (Glu), is thought to be the major excitatory neurotransmitter in the vertebrate central nervous system and a key participant in the synaptic plasticity underlying learning and memory. Additionally, prolonged exposure of neurons to Glu has clear toxic consequences prompting hypotheses regarding the role of this agent in several neuropsychiatric syndromes. The related excitatory and toxic actions of Glu make it important to understand factors involved in regulating responses mediated by this transmitter system. In this proposal for a Level II Research Scientist Development Award experiments are proposed which will investigate pre- and postsynaptic factors involved in regulating the action of Glu as a synaptic transmitter in two in vitro preparations - cultured postnatal rat hippocampal neurons and rat hippocampal slices. One set of experiments will investigate the single channel correlates of the rapid postsynaptic receptor desensitization which occurs at ionotropic non-N-methyl-D-aspartate receptors using the lectin wheat germ agglutinin as a tool to inhibit desensitization. These experiments will examine whether desensitization results from a change in the single channel conductance, the probability of channel opening or the number of ion channels. A second set of experiments will investigate the role of desensitization in regulating the time course and efficacy of excitatory synaptic responses. Thirdly, we will examine the modulation of presynaptic Glu release by examining the actions of the psychotherapeutic drug lithium, which enhances excitatory synaptic responses by an apparent presynaptic mechanism. Finally, the ability of physiological concentrations of EAA to modulate hippocampal long-term potentiation, a model of synaptic plasticity, will be investigated. These studies have the potential to shed light on the regulation of synaptic Glu responses and on ways that Glu-mediated functions are subject to pharmacological and pathological alteration.
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