The receptors for certain amino acids have complex roles in the brain in learning, memory and even in inducing neuronal death. These receptors are being studied for their possible role in various age-associated diseases including Alzheimer's disease. The major emphasis of this project is the investigation of the role of excitatory amino acids (EAA) receptors in neurodegenerative disorders of aging. This year we discovered a splice variant form of the NMDA subtype of EAA receptor. This isoform contains a deletion of 35 amino acids in the carboxy tail of the molecule. The deleted amino acids were found to be encoded on a separate exon in the rat genome. The deletion form is predominantly expressed in the cerebellum and brain stem while the full length form is found in rostral regions of the brain. We have found that both undifferentiated and differentiated PC-12 cells express both flip and flop forms of the GLUR-2 submit of the AMPA receptor, and that some previously uncharacterized splicing of this gene may occur in cell culture. We have just initiated work to clone and characterize the promoter region of the NMDA receptor. This work is critical in determining how the expression of the NMDA receptor is regulated at the molecular level. Finally, neural cell culture is being explored to examine NMDA and AMPA receptor subunit changes under conditions mimicking neurotoxicity and neuroprotection.
