TY - JOUR T1 - Role of Estrogen Receptor α and β in Preserving Hippocampal Function during Aging JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2671 LP - 2683 DO - 10.1523/JNEUROSCI.4937-12.2013 VL - 33 IS - 6 AU - Xiaoxia Han AU - Kristina K. Aenlle AU - Linda A. Bean AU - Asha Rani AU - Susan L. Semple-Rowland AU - Ashok Kumar AU - Thomas C. Foster Y1 - 2013/02/06 UR - http://www.jneurosci.org/content/33/6/2671.abstract N2 - 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 ERα 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 ERαKO mice was similar to WT mice 6 h after a single estradiol treatment. In middle-age ERαKO 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 ERαKO mice, ERβKO mice exhibited a basal hippocampal gene profile similar to WT mice treated with estradiol and, in the absence of estradiol treatment, young and middle-age ERβKO mice 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 ERα-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 hippocampal-dependent memory. Thus, our results indicate that ERα and ERβ interact with hormone levels to regulate transcription involved in maintaining hippocampal function during aging. ER -