Role of Estrogen Receptor α and β in Preserving Hippocampal Function during Aging

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