Here we provide the first evidence, to our knowledge, that estradiol (E 2) affects learning and memory via the newly discovered estrogen receptor ␤ (ER␤). In this study, ER␤ knockout (ER␤KO) 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, ER␤KOs given the low dose of E 2 were delayed in learning acquisition, and ER␤KOs administered the higher dose of E2 failed to learn the task. These data show that ER␤ is required for optimal spatial learning and may have implications for hormone replacement therapy in women.T he steroid hormone estradiol (E 2 ) either is required for or significantly modulates many behaviors, including cognitive behaviors (1-9). Learning tasks that involve reference memory tend to be impaired by E 2 (1,7,8). In contrast, low levels of E 2 may facilitate working memory (5, 9). In women, changes in ability on visuospatial tasks and memory recall over the menstrual cycle have been documented (10, 11). Also, beneficial effects of estrogen replacement on cognition have been noted in normally aging women (12, 13) and in women suffering from dementia associated with Alzheimer's disease (14,15).How estrogen acts on learning and memory is not clear. Estrogen binding has been reported throughout the rodent brain, including the hippocampus and cortex (16). Both characterized nuclear estrogen receptors (ER␣ and -␤) are present in extrahypothalamic regions (17,18). In addition, in vitro work suggests that estrogen acts in a nongenomic fashion in hippocampal tissues (19,20). Mice lacking functional ER␣ have severe deficits in several aspects of reproduction, including behavior (21-24). On the other hand, ER␤ knockout mice (ER␤KO) are subfertile, and sexual behavior is normal (25, 26). Thus, there has been speculation that ER␤ regulates estrogen's nonreproductive functions in the central nervous system (21, 27, 28).Here we describe our work on spatial learning in female ER␤KO mice. When treated with doses of E 2 that do not affect learning in wild-type (WT) littermates, ER␤KO mice had impaired ability to escape from the Morris water maze. Interactions between ER␣ and -␤ may contribute to the learning response; to test the hypothesis that lack of ER␤ influences the level of ER␣ protein, mouse brains were examined for ER␣ immunoreactivity (ER␣-ir), with emphasis on the hippocampus (HIPP). MethodsAnimals. Female mice (ages 5-7 mos) were of mixed 129͞J and C57BL͞6J background. Subjects were generated by crossing heterozygotic mating pairs carrying a single copy of the disrupted ER␤ gene (25). The resulting offspring were genotyped by PCR amplification of tail DNA. WT and ER␤ disrupted (ER␤KO) littermates were used in these studies. The ER␤ gene disruption was created by Neo insertion into exon 3 (25), thus the following three primers were used: one from intron 2 (5Ј-GGAGTAGAAACAAGCAATCCAGACATC-3Ј), a...

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