EXCITATORY AMINO ACIDS--ROLE IN CNS DISORDERS

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The long range goal of our program project is to study events that occur at the excitatory amino acid (EAA) synapse and to use this knowledge to provide: (1) more in-depth understanding of CNS functions in health and disease at both the cellular and systems level, and (2) new therapeutic opportunities in treating disorders of CNS function. To achieve this goal, a set of strategies will be used and these are as follows: (1) New information will be sought on EAA receptor subtype (or subtypes) responsible for mediating a specific function and/or pathological state at identified CNS sites using pharmacological tools, specific antibodies to EAA subtypes, and EAA receptor specific cDNA probes; the focus here will be on both EAA ionotropic and metabotropic receptors; (2) New information will be sought on the cascade of events that occur inside neurons (and glia) after activation of specific EAA receptors; (3) New information will be sought on the cellular and functional consequences of alterations in the allosteric modulatory sites of the NMDA and AMPA receptor subtypes, especially, on the activation of an allosteric site on the AMPA receptor complex with cyclothiazide; (4) New information will be sought on the presynaptic mechanisms in EAA-mediated excitatory neurotransmission and neurotoxicity including information on the role of glutamate release (using BW1003C87), uptake (using L-Trans-PDC), NAAG release and extracellular hydrolysis to produce glutamate, and NAAG and glutamate as putative presynaptic inhibitors acting by inhibiting adenylate cyclase; (5) New information will be sought on the role of other neurotransmitter systems that may regulate the release of EAA(s) or NAAG, or that may provide a post-synaptic effect which modulates the EAA response; and (6) New information will be sough on whether significant interactions between ionotropic and metabotropic receptors exist, and the impact of such interactions on synaptic transmission. By utilizing these six research strategies we will gain a more in-depth understanding of the role of CNS EAA synaptic transmission in health and disease, and will increase the therapeutic opportunities for treating disorders of CNS function.