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.