Novel effects of estradiol and estrogen receptor alpha and beta on cognitive function.

Estrogen influences the development of memory function in humans and rodents and can modulate memory in adults. In these studies we examined the role of the estrogen receptors alpha (ERalpha) and beta (ERbeta) in mediating performance on a hippocampal-dependent, hormone-sensitive task, inhibitory avoidance (IA). Ovariectomized (OVX) estrogen receptor-alpha-knockout (ERalphaKO) mice displayed impaired performance on the IA task and OVX heterozygotic (HET) mice exhibited performance that was intermediate between ERalphaKO and wild-type (WT) mice. Impaired performance by ERalphaKO mice was rescued by E(2) treatment. The ER antagonist, tamoxifen, did not block enhancement of retention by E(2) suggesting that E(2) mediated modulation of memory is not caused by known genomic receptor mechanisms. In contrast to ERalphaKO mice, IA performance by OVX estrogen receptor-beta-knockout (ERbetaKO) mice was not compromised. The results indicate an important role for ERalpha, relative to ERbeta, in the establishment of cognitive function and suggest that E(2) modulates memory function via a novel estrogenic mechanism.