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 β (ERβ). In this study, ERβ knockout (ERβKO) 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, ERβKOs given the low dose of E(2) were delayed in learning acquisition, and ERβKOs administered the higher dose of E(2) failed to learn the task. These data show that ERβ is required for optimal spatial learning and may have implications for hormone replacement therapy in women.