Memory loss occurs during normal aging in humans. The N-methyl-D-aspartate (NMDA) receptor, an excitatory amino acid (EAA) receptor, is believed to play an important role in memory and learning processes. There is an apparent loss of 3H-glutamate binding to NMDA receptors in the brains of old BALB/c and C57B1 mice. The channel protein of the NMDA receptor complex, however, appears to be spared. This suggests that the NMDA receptor may still be present in these aged animals. The hypothesis addressed by this proposal is that there is a change in affinity of NMDA receptors for glutamate that is alterable experimentally. This alteration could be accomplished with glycine or its analogs since glycine enhances NMDA receptor functions [25, 60]. The proposed investigation is described by the following five specific aims to: 1) Determine whether the entire NMDA receptor complex is lost during aging with the use of autoradiographic techniques. 2) Determine whether NMDA binding sites are lost during aging or whether there is a change in their affinity for glutamate by determining the total number of binding sites, the affinity and the effect of glycine on the affinity of those sites for glutamate in young and old animals. 3) Determine what other age-related factors could account for decreases in binding to NMDA receptors by examining age-related differences in glycine and protein concentrations. 4) Determine whether there is an alterable decrease in electrophysiological responses involving NMDA receptors with aging. Hippocampal slices will be used to determine age-related differences in NMDA receptor function by examining stimulus-evoked responses and induction of long-term potentiation which involve NMDA receptors. 5) Determine whether there is an alterable change in the performance in a spatial memory test with aging using the Morris water maze test. The results of these studies will provide important information on the fate of the NMDA receptor complex and its associated functions during the aging process and the reversibility of these age-related changes. These results should have relevance to the memory loss found in normal aging in humans and to at least some of the memory decline experienced by Alzheimer's patients.
