SUBUNIT CHANGES IN AGING NMDA RECEPTORS AFFECT MEMORY
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DESCRIPTION (Adapted from applicant's abstract): Humans experience declines in memory performance as they age. Some of these declines are benign, but others can interfere with independent living. Elucidating the causes for memory decline during the aging process will allow us to design interventions that can prolong the quality and safety of life in old age. The N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, is important in learning and memory processes and has been shown to decline in function in both humans and rodents as they age. The NMDA biding site appears to be more vulnerable to the aging process than other ionotropic glutamate receptors and other binding sites on the NMDA receptor complex and the changes in the rostral cerebral cortex correlate with declines in memory function. One potential explanation for this could be a change in the subunit composition of the NMDA receptor complex during aging. Changes in one or more subunits could alter the channel and pharmacological properties of the NMDA receptor, which could alter the overall ability of the receptor to contribute to memory processes. The hypothesis addressed by the proposal is that age-related declines in memory are induced by changes in the expression of subunits for the NMDA receptor during the aging process. The hypothesis will be addressed by the following four Specific Aims to: 1) Determine whether there are changes in mRNA expression for NMDA subunits during aging by using in situ hybridization and nuclease protection assays. 2) Determine whether there are changes in the expression of NMDA subunit proteins during aging by performing semi-quantitative Western Blotting. 3) Determine whether age-related changes in NMDA subunit expression are associated with spatial memory declines by comparing mRNA and protein results with reference (Morris water maze) and working (Olton radial arm maze) memory tasks. 4) Determine whether inhibiting the expression of NMDA subunit(s) in young animals induces similar deficits in memory performance to those seen in aged animals with the use of antisense oligonucleotide injections and memory testing. These studies will provide information about whether interventions to partially or fully restore memory functions in aged individuals should be aimed at restoring the NMDA receptor subunit expression that is present in the young. These results will aid our efforts to improve memory functions during the normal aging process and potentially delay some of the declines seen in Alzheimer's disease. This information will also enhance our knowledge about the role of specific NMDA receptor subunits in learning and memory processes.
