The amino acid glutamate is the major excitatory synaptic transmitter in the vertebrate central nervous system (CNS). A class of glutamate-gated ion channels responsive to the selective agonist N-methyl-D-aspartate (NMDA) is thought to play crucial roles in the neurotoxicity mediated by glutamate (excitotoxicity). Excitotoxicity, in turn, has been implicated in neuronal death in focal cerebral ischemia, epilepsy, CNS trauma, and several neurodegenerative neurological disorders such as Huntington's disease, AIDS dementia, and Parkinsonism. NMDAR-L (NMDA-receptor-like) is a recently isolated gene which shares homology to NMDA-receptor subunits NR1 and NR2. The expression of the rat NMDAR-L gene is temporally and regionally restricted. Beginning in late embryogenesis and continuing through the first postnatal week, NMDAR-L is highly expressed in areas such as the cerebral cortex, the hippocampus and the thalamus. In order to identify in vivo functions of NMDAR-L, mutant (knockout) mice with targeted disruption of the NMDAR-L gene have been generated in my laboratory. Whole-cell patch recordings of acutely dissociated cortical neurons revealed that the mutant neurons exhibit larger NMDA-evoked current than wild-type cells. In addition, NMDAR-L protein is enriched in postsynaptic density (PSD) fractions of the brain extract. Moreover, NMDAR-L protein was co-immunoprecipitated with each of NR1 and NR2 subunits when expressed in COS cells. These results strongly suggest that NMDAR-L modifies NMDAR functions in vivo by physically interacting with NR1 and NR2. Finally, the dendritic morphology of cortical neurons was significantly altered in the NMDAR-L knockout mouse. Specifically, the number of dendritic spines was increased, and the size of spine structure was enlarged in mutant mice. This finding indicates that NMDAR-L may regulate the number of synapses formed onto cortical neurons during development. In our proposed study, with the use of the knockout mice, the role of NMDAR-L in synapse formation and the pathogenesis of excitoxicity will be examined.
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