This review presents evidence for the idea that the expression of estrogen receptor alpha and beta (ERα and ERβ) interacts with the level of estradiol (E2) to influence the etiology of age-related cognitive decline and responsiveness to E2 treatments. There is a nonmonotonic dose response curve for E2 influences on behavior and transcription. Evidence is mounting to indicate that the dose response curve is shifted according to the relative expression of ERα and ERβ. Recent work characterizing age-related changes in the expression of ERα and ERβ in the hippocampus, as well as studies using mutant mice, and viral mediated delivery of estrogen receptors indicate that an age-related shift in ERα/ERβ expression, combined with declining gonadal E2 can impact transcription, cell signaling, neuroprotection, and neuronal growth. Finally, the role of ERα/ERβ on rapid E2 signaling and synaptogenesis as it relates to hippocampal aging is discussed.
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