The proposed program of research, clinical activity, and academic exposure should provide the primary investigator with a strong foundation for research in basic neurology and movement disorders. Research on mechanisms of glutamatergic neurotransmission and excitotoxicity will form the core of the proposed program. Glutamate induced excitotoxicity through the N- methyl-D-aspartate (NMDA) receptor has been implicated in many chronic and acute neurologic disorders including hypoxic-ischemic damage, Huntington's disease, secondary damage from head trauma, glutaric acidemia, hyperammonemia and other central nervous system disorders. The exact pathologic character of excitotoxic damage varies depending on many factors including developmental stage and brain region. One possible explanation for such variations in excitotoxicity is variability in NMDA receptor structure and pharmacology. Understanding the biochemical and pharmacological basis of heterogeneity in NMDA receptors may elucidate the mechanistic reasons for variability in excitotoxic mechanisms. A series of cDNA's have been cloned which are proposed to encode NMDA receptor subunit proteins. These diverse cDNA's suggest possible mechanisms for production of NMDA receptor subtypes. This proposal will use in vitro model systems to examine the biochemical and pharmacological heterogeneity of NMDA receptors composed of different subunits. NMDA receptor assembly will be modeled in transfected cells and then in cells with a neuronal phenotype. Biochemistry and pharmacology of the NMDA receptors in these systems will be examined. These findings will be extended to determine the role of specific NMDA receptor subunits in excitotoxicity and thus provide a rational basis for design of pharmacological agents acting at NMDA receptor subtypes.
