CIRCUIT-SPECIFIC ALTERATIONS OF N-METHYL-D-ASPARTATE RECEPTOR SUBUNIT-1 IN THE DENTATE GYRUS OF AGED MONKEYS

Age-associated memory impairment occurs frequently in primates, Based on the established importance of both the perforant path and N-methyl- D-aspartate (NMDA) receptors in memory formation, we investigated the glutamate receptor distribution and immunofluorescence intensity withi n the dentate gyrus of juvenile, adult, and aged macaque monkeys with the combined use of subunit-specific antibodies and quantitative confo cal laser scanning microscopy, Here we demonstrate that aged monkeys, compared to adult monkeys, exhibit a 30.6% decrease in the ratio of NM DA receptor subunit 1 (NMDAR1) immunofluorescence intensity within the distal dendrites of the dentate gyrus granule cells, which receive th e perforant path input from the entorhinal cortex, relative to the pro ximal dendrites, which receive an intrinsic excitatory input from the dentate hilus, The intradendritic alteration in NMDAR1 immunofluoresce nce occurs without a similar alteration of non-NMDA receptor subunits, Further analyses using synaptophysin as a reflection of total synapti c density and microtubule-associated protein 2 as a dendritic structur al marker demonstrated no significant difference in staining intensity or area across the molecular layer in aged animals compared to the yo unger animals, These findings suggest that, in aged monkeys, a circuit -specific alteration in the intradendritic concentration of NMDAR1 occ urs without concomitant gross structural changes in dendritic morpholo gy or a significant change in the total synaptic density across the mo lecular layer, This alteration in the NMDA receptor-mediated input to the hippocampus from the entorhinal cortex may represent a molecular/c ellular substrate for age-associated memory impairments.