The role of acetylcholine in the estrogen-induced increase in hippocampal NMDA receptor binding and in the associated enhancement of working memory performance
Description
Elevated levels of circulating estrogen in female rats have been associated with increased spine and synapse density and increased levels of NMDA receptor binding in area CA1 of the hippocampus, as well as with enhancements on certain tasks of learning and memory. Results of recent studies indicate that estrogen induces morphological changes in CA1 by reducing the activity of the inhibitory neurotransmitter, GABA, in hippocampal neurons. However, the mechanism by which estrogen acts on GABAergic neurons is unknown. Interestingly, the neurotransmitter acetylcholine acts at the M2 subtype of the muscarinic receptor to inhibit GABA release in the hippocampus and the activity of acetylcholine has been shown to be increased by circulating estrogen. The present objectives were to determine the role of acetylcholine in the estrogen-induced increase in NMDA receptor binding in CA1 of the hippocampus and to investigate the relationship between increased NMDA binding in CA1 and improvements in working memory performance In the current experiments, elevating endogenous levels of acetylcholine in ovariectomized rats via chronic administration of physostigmine, an acetylcholine sterase inhibitor, resulted in increased NMDA binding in CA1, an increase that was comparable to the increase induced by estrogen. Additionally, the administration of BIBN-99, an M2 receptor antagonist, completely blocked the ability of estrogen and diminished the ability of physostigmine to affect levels of hippocampal NMDA binding. An important relationship was revealed between the estrogen-induced morphological changes in CA1 and performance on a task that measured memory. The regimen of estradiol replacement shown to increase NMDA binding in CA1 resulted in enhanced working memory performance as assessed in an eight-arm radial maze. In addition, the estradiol-induced enhancement in performance was blocked by administration of BIBN-99 which also blocked the increase in NMDA binding The results of the experiments in the present study indicate that acetylcholine acts at the M2 muscarinic receptor to bring about the estrogen-induced increase in NMDA receptor binding in CA1 of the hippocampus as well as the associated improvements in working memory performance. These results suggest a mechanism by which estrogen may act to inhibit GABA release resulting in morphological changes in CA1 of the hippocampus