Estrogen modulates synaptic N-methyl-D-aspartate receptor subunit distribution in the aged hippocampus

Estrogen interacts with N-methyl-D-aspartate (NMDA) receptors to regulate multiple aspects of morphological and functional plasticity. In hippocampus, estrogen increases both dendritic spine density and synapse number, and NMDA antagonists block these effects. Thus, estrogen-mediated hippocampal plasticity may be of particular importance in the context of age-related changes in endocrine status and cognitive performance. NR1 levels per synapse are increased in CA1 by estrogen in aged rats but not young rats, although no information is available on estrogen-induced synaptic alterations in other NMDA receptor subunits that might impact function. Therefore, the present study was designed to investigate the effect of estrogen on the synaptic and subsynaptic distributions of the NMDA receptor subunits, NR2A and NR2B in CA1 pyramidal cells, within the context of aging. Our results demonstrated that the overall synaptic levels of NR2A and NR2B are similar in young and aged female rats, regardless of estrogen treatment. However, in the aged CA1, estrogen restores NR2B levels back to young levels in the lateral portions of the active synaptic zone. Thus, estrogen may impact the mobility of NMDA receptors across the synapse and, in the process, restore a more youthful synaptic profile. These findings have important implications for the mechanism of estrogen-induced alterations in NMDA receptor-mediated processes, particularly in the context of aging.