GENETIC APPROACH TO EXCITATORY TRANSMISSION

Burnham Institute For Medical Research, La Jolla CA

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Abstract

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-excitotoxicity). Excitotoxicity, in turn, has been implicated in neuronal death in focal cerebral ischemia, epilepsy, CNS trauma, and several neurodegenerative disorders such as Huntington's disease, AIDS dementia and Parkinsonism. NR3A (formerly called NMDAR-like khi-2) is a recently cloned glutamate receptor subunit which shares high homology to NMDA receptor subunits NR1 and NR2. The expression of the rat NR3A gene is temporally and regionally restricted. Beginning in late embryogenesis and continuing the first postnatal order to identify in vivo functions of NR3A, mutant (knock out) mice with targeted disruption of the NR3A gene have been generated in my laboratory. Whole-cell recordings with patch electrodes of acutely dissociated cortical neurons (performed in conjunction with Project of this Program Project Grant) revealed that the mutant neurons density (PSD) fractions of brain extracts from wild-type mice. Moreover, NR3A protein was co-immunoprecipitated with NR1 and NR2 subunits from these brain extracts. Based on these new data, we propose that NR3A is a novel regulatory subunit of NMDAR channels. Finally, in our preliminary experiments we found that the dendritic morphology of cortical neurons is significantly altered in the NR3A knockout mouse. Specifically, the number of dendritic spines is increased, and the size of the spines was enlarged in the mutant mice. This finding suggests that NR3A may regulated the number of synapses formed onto cortical neurons during development. In our proposed studies, using the knockout mice, the role of NR3A in synapse formation and the pathogenesis of excitotoxicity will be examined.