Subunit Changes in Aging NMDA Receptors Affect Memory

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DESCRIPTION (provided by applicant): People suffer memory losses as they age that interfere with independent living. Discovering the causes for memory decline during the aging process will allow us to design interventions that can prolong both the quality and safety of life in old age. The N-methyl-D-aspartate (NMDA) receptor, a type of glutamate receptor, is important in learning and memory processes and has been shown to decline in function in both humans and rodents as they age. We have found changes during aging in the expression of some of the subunits that comprise the receptor and some of these changes are related to memory declines. Changes in one or more subunits can 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 that will be addressed by this proposal is that complex changes in the expression patterns of specific subunits of the NMDA receptor lead to age-related declines in learning and memory. The hypothesis will be addressed by the following four Specific Aims to: 1) Determine the functional consequences of the age-related decline in epsilon2 subunit expression within different brain regions, 2) Determine whether the relationship between age-related changes in the zeta1 subunit expression and spatial memory declines are associated with changes in the expression of specific zeta1 splice variants, 3) Determine whether changes in synaptic expression of the receptor subunit proteins are related to spatial memory declines during aging, 4) Differentiate the effects on NMDA receptor expression of three aging interventions (caloric restriction, learning experience, and exercise) that can each enhance cognitive abilities. Behavioral testing in each aim will examine both reference and working memory. These studies will provide information about whether interventions to partially or fully restore memory functions in aged individuals should be aimed at restoring specific NMDA receptor subunit expression levels that are present in the young and/or targeting specific brain regions. 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 within specific brain regions in learning and memory.