Estrogen receptor beta regulates sexually dimorphic neural responses to estradiol.

Estrogen receptors (ERs) mediate many sexual dimorphisms in the neuroendocrine system and in behavior. We examined the consequences of the loss of functional estrogen receptor beta (ERbeta) on two sexually differentiated neural responses to estrogen. In wild type (WT) male mice, but not in females, estradiol (E(2)) treatment decreased estrogen receptor alpha immunoreactive (ERalpha-ir) cell numbers in the arcuate nucleus (ARC), the preoptic area (POA), and the ventromedial nucleus (VMN). These sex differences were reversed in ERbeta knockout (ERbetaKO) mice. Castrated ERbetaKOs did not show any change in ERalpha-ir cell number after E(2) treatment. Yet, E(2) decreased ERalpha-ir cell number in ovariectomized ERbetaKOs. Estradiol treatment increased progesterone receptor immunoreactive (PR-ir) cell number in WT female VMN and POA, but no change was noted in brains of WT castrates. In ERbetaKO mice the opposite relationship was found, E(2) treatment increased PR-ir cell number in male, but not in female, brains. Our results show that ERbeta influences several sexually dimorphic neural responses to estrogen. Moreover the data clearly show that ERbeta can modulate neural expression of ERalpha.

Receptor blockade reveals a correspondence between hippocampal-dependent behavior and experience-dependent synaptic enhancement.

This study examined the involvement of N-methyl-D-aspartate receptors (NMDARs) in experience-dependent synaptic plasticity. Rats chronically received an NMDA receptor antagonist (AP5) or saline (SAL) and were exposed to individual cages (IC) or environmental enrichment (EC). AP5 impaired measures of hippocampal-dependent behavior and increased locomotor activity. Perforant path synaptic strength, measured in the in vitro hippocampal slice, was increased and long-term potentiation (LTP) was decreased for EC+SAL animals. The experience-dependent effects on synaptic function were inhibited by drug treatment. Measures of synaptic strength were correlated with hippocampal-dependent behavior and synaptic plasticity for EC animals. The results suggest a relationship between hippocampal-dependent behavior and experience-dependent modification of perforant path synaptic function through NMDAR activation.

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.

Sex with knockout models: behavioral studies of estrogen receptor alpha.

Estrogens are an important class of steroid hormones, having multiple targets, in the body and brain, and exerting ubiquitous effects on behavior. At present, two estrogen receptors (ERalpha and beta) 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 alpha (ERalpha) gene, to study the mechanisms by which estrogens mediate behaviors. There are pronounced ramifications of ERalpha gene disruption on behavior. First, female ERalpha knockout (ERalphaKO) 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 ERalphaKOs. Third, male ERalphaKOs do not exhibit the same social preferences for female mice as do wildtype (WT) littermates. Thus, the ERalpha is essential for normal expression of sexual behaviors. In addition, gonadectomized ERalphaKO 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 ERalphaKO mice, suggesting that estrogens effects on learning in adult females involves the ERalpha. Based on these data we hypothesize that ERalpha mediates many of the effects of estrogen on sexual behavior, learning, and memory.

Examination of estradiol effects on the rapid estradiol mediated increase in hippocampal synaptic transmission in estrogen receptor alpha knockout mice.

Hippocampal slices from rats exhibit a rapid increase in basal synaptic transmission following 17 beta-estradiol (E(2)) application. In the current study we examined the role of the classic genomic receptor, estrogen receptor alpha (ER alpha), in mediating E(2) effects on synaptic transmission. E(2) (100 pM) increased the extracellular synaptic response in hippocampal slices from gonadectomized male and female mice lacking a functional ER alpha knockout (ER alpha KO) and wild-type (WT) littermates. No sexually dimorphic differences were observed, however, the increase in the field potential was more pronounced in WT mice. ER antagonists did not block E(2) mediated growth of the synaptic response in ER alpha KO mice. The results suggest that the rapid effect of E(2) on synaptic transmission is not mediated by ER alpha, however, ER alpha appears to modulate non-genomic influences on synaptic transmission.

Sex differences in the activational effect of ERalpha on spatial learning.

This study investigated the role of the estrogen receptor alpha (ERalpha) in mediating performance on a spatial discrimination task, the Morris water maze. Spatial discrimination on this water escape task was examined in eight groups of gonadectomized mice. Male and female wild-type (WT) and littermate mice lacking functional copies of the ERalpha gene (ERalphaKO), were treated with estradiol benzoate (EB) or sesame oil vehicle. Subjects were trained on the water escape task over a 4-day period (four trials per block, three blocks per day). Latency to find the hidden platform was measured. Only female WT mice treated with EB failed to learn this spatial discrimination task. All males, WT and ERalphaKO treated with EB or oil exhibited decreased latencies across blocks of trials, WT females treated with oil, and ERalphaKO females, regardless of treatment, learned the spatial discrimination task. In order to eliminate motivational or sensory-motor impairments as a factor in describing the poor spatial discrimination performance of WT females treated with EB, the cue version of the water maze task was employed. Results from the cue phase of the task indicate that EB and oil-treated WT females exhibited a similar decrease in escape latencies across blocks of trials, indicating good cue discrimination performance. Taken together, the results indicate that ERalpha activation impairs acquisition of spatial discrimination of the water escape task, but not cue discrimination, in female mice. Because ligand-bound ERalpha appears to operate differently in male and female mice we hypothesize that the ability of ERalpha to affect learning is organized during development.