Disruption of estrogen receptor β gene impairs spatial learning in female mice

Here we provide the first evidence, to our knowledge, that estradiol (E-2) affects learning and memory via the newly discovered estrogen receptor beta (ERbeta). In this study, ERbeta knockout (ERbetaKO) and wild-type littermates were tested for spatial learning in the Morris water maze after ovariectomy, appropriate control treatment, or one of two physiological doses of E-2. Regardless of treatment, all wild-type females displayed significant learning. However, ERbetaKOs given the low dose of E-2 were delayed in learning acquisition, and ERbetaKOs administered the higher dose of E-2 failed to learn the task. These data show that ERbeta is required for optimal spatial learning and may have implications for hormone replacement therapy in women.