Role of estrogen receptor α and β in preserving hippocampal function during aging

The expression of the ERα and ERβ estrogen receptors in the hippocampus may be important in the etiology of age-related cognitive decline. To examine the role of ERβ and ERβ in regulating transcription and learning, ovariectomized wild-type (WT) and ERα and ERβ knockout (KO) mice were used. Hippocampal gene transcription in young ERβ KOmice was similar to WTmice 6 h after a single estradiol treatment. In middle-age ERβ KO mice, hormone deprivation was associated with a decrease in the expression of select genes associated with the blood-brain barrier; cyclic estradiol treatment increased transcription of these select genes and improved learning in these mice. In contrast to ERαKOmice, ERβ KOmice exhibited a basal hippocampal gene profile similar to WT mice treated with estradiol and, in the absence of estradiol treatment, young and middle-age ER β KOmice exhibited preserved learning on the water maze. The preserved memory performance of middle-age ERβKO mice could be reversed by lentiviral delivery of ERβ to the hippocampus. These results suggest that one function of ERβ is to regulate ERβ-mediated transcription in the hippocampus. This model is supported by our observations that knockout of ERβ under conditions of low estradiol allowed ERα-mediated transcription. As estradiol levels increased in the absence of ERα, we observed that other mechanisms, likely including ERβ, regulated transcription and maintained hippocampaldependent memory. Thus, our results indicate that ERα and ERβ interact with hormone levels to regulate transcription involved in maintaining hippocampal function during aging.