N-methyl-D-aspartate receptor mRNA levels change during reproductive senescence in the hippocampus of female rats

Estrogen interacts with N-methyl-D-aspartate (NMDA) receptors to regulate m ultiple aspects of morphological and functional plasticity. In the hippocam pus, estrogens increase both dendritic spine density and synapse number, an d NMDA antagonists block these effects. This plasticity in the hippocampus mediated by estrogen may be of particular importance in the context of agin g when estrogen levels change and cognitive function is often impaired. The refore, the present study was designed to investigate effects of aging and reproductive status on NMDA receptor (NR) subunit mRNA levels in the hippoc ampus. NR1, MR2A, and NR2B mRNA levels were measured by RNase protection as say in young (3-4 month), middle-aged (12-13 month), and aged (24-25 month) Sprague-Dawley rats in different phases of the estrous cycle in cycling an imals and in acyclic subjects. Our results demonstrated that NMDA receptor subunit mRNA levels were much more prominently affected by the chronologica l age than by the reproductive status of the animals. Age-related changes w ere observed in NR1, NR2A, and NR2B in the ventral hippocampus and in NR1 a nd NR2B in the dorsal hippocampus. However, the only relationship with repr oductive status was seen for NR1 mRNA, and this was restricted to the ventr al hippocampus. An interaction between chronological age and reproductive s tatus was found, with higher levels of NR1 mRNA seen in young animals in pr oestrus than in those in diestrus I (high and low estrogen levels, respecti vely). However, this relationship was not seen in the aged subjects. These results demonstrate that the hippocampus is subjected to age-related altera tions in NMDA receptor subunit mRNA levels and that animals of different ag es are influenced differently by reproductive status. This shift in the NMD A receptor mRNA levels may be a possible molecular mechanism contributing t o alterations in cognitive behavior during normal aging. (C) 2001 Academic Press.