Glu is the major fast excitatory transmitter in the mammalian CNS and normally participates in information processing and memory. Alterations in the Glu system may be involved in several disorders including epilepsy, ischemic brain damage and schizophrenia. It is therefore important to understand how Glu neurotransmission is regulated and modulated. In this request for a Senior Scientist Award, experiments are described that will address several questions concerning Glu-mediated synaptic transmission in in vitro hippocampal cell cultures and hippocampal slices. First, using a preparation of hippocampal cells grown on microislands, the role of Glu transporters in controlling the duration that receptors are exposed to Glu following synaptic release will be examined. These studies will take advantage of recent developments in the molecular biology of Glu transporters to examine the relative contributions of neuronal and glial transporters. Second, specific experiments will examine how Glu regulates its own synaptic efficacy via postsynaptic receptor desensitization and modulation of presynaptic release. Emphasis will be placed on how Glu transmission is altered by changes in extracellular Glu levels and repeated synaptic activation. Third, using hippocampal slices, the effects of low concentrations of agonists at N-methyl-D-aspartate (NMDA) receptors on the threshold for inducing long-term potentiation (LTP) and long-term depression (LTD) in the CAI region will be examined. These studies will extend information from the first two sets of experiments and will probe recent findings regarding the desensitization of synaptic NMDA receptors. Finally, the ability of certain steroids to modulate Glu receptors and to alter synaptic transmission will be examined. These studies will use steroid enantiomers to determine whether steroids act at specific sites on Glu receptor proteins or via effects on membrane lipids. It is hoped that these experiments will provide insights into the function and regulation of Glu-mediated synaptic transmission in the hippocampus and that this information will be helpful in devising more effective treatment strategies for patients with neuropsychiatric disorders.
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