Sex with knockout models: Behavioral studies of estrogen receptor

Estrogens are an important class of steroid hormones, having multiple targets, in the body and brain, and exerting ubiquitous effect on behavior. At present, two estrogen receptors (ERα and β) have been cloned and sequenced in mammals. In the brain these receptors are regionally specific, but both have widespread distributions, which are largely non-overlapping. Given the newly emerging complexities of estrogen's mechanisms of action it is important to distinguish which pathways are involved in modifying which behaviors. We use a knockout mouse, lacking functional copies of the estrogen receptor α (ERα) gene, to study the mechanisms by which estrogens mediate behaviors. There are pronounced ramifications of ERα gene disruption on behavior. First, female ERα knockout (ERαKO) mice do not display normal feminine sexual behavior. Second, treatment of adult mice with androgens promotes masculine sexual behavior in both sexes. However, male-typical sexual behavior is severely compromised in male and female ERαKOs. Third, male ERαKOs do not exhibit the same social preferences for female mice as do wildtype (WT) littermates. Thus, the ERα is essential for normal expression of sexual behaviors. In addition, gonadectomized ERαKO and WT mice rapidly learn to escape from the Morris water maze. Exogenous estrogen treatment prevents WT females from learning this task, yet, has no effect in ERαKO mice, suggesting that estrogens effects on learning in adult females involves the ER2a. Based on these data we hypothesize that ERα mediates many of the effects of estrogen on sexual behavior, learning, and memory.