Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats

Hippocampal N-methyl-D-Aspartate (NMDA) receptors mediate mechanisms of cel lular plasticity critical for spatial learning in rats. The present study e xamined the relationship between spatial learning and NMDA receptor express ion in discrete neuronal populations, as well as the degree to which putati ve age-related changes in NMDA receptors are coupled to the effects of norm al aging on spatial learning. Young and aged Long-Evans rats were tested in a Morris water maze task that depends on the integrity of the hippocampus. Levels of NR1, the obligatory subunit for a functional NMDA receptor, were subsequently quantified both biochemically by Western blot in whole homoge nized hippocampus, and immunocytochemically by using a high-resolution conf ocal laser scanning microscopy method. The latter approach allowed comprehe nsive, regional analysis of discrete elements of excitatory hippocampal cir cuitry. Neither method revealed global changes, nor were there region-speci fic differences in hippocampal NR1 levels between young and aged animals. H owever, across all subjects, individual differences in spatial learning abi lity correlated with NR1 immunofluorescence levels selectively in CA3 neuro ns of the hippocampus. Parallel confocal microscopic analysis of the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid ( AMPA) receptor failed to reveal reliable differences as a function of age o r spatial learning ability. This analysis linking age, performance, and NR1 levels demonstrates that although dendritic NR1 is generally preserved in the aged rat hippocampus, levels of this receptor subunit in selective elem ents of hippocampal circuitry are linked to spatial learning. These finding s suggest that NMDA receptor abundance in CA3 bears a critical relationship to learning mediated by the hippocampus throughout the life span. J. Comp. Neurol. 432:230-243, 2001. (C) 2001 Wiley-Liss, Inc.