Low Doses of 17 alpha-Estradiol and 17 beta-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17 alpha- and 17 beta-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

Estrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. In particular, 17 beta-estradiol can improve, impair, or have no effect on hippocampus-dependent learning and memory depending on dose and time of administration. The effects of other forms of estrogen, such as estrone and 17 alpha-estradiol, on hippocampus-dependent learning have not been as thoroughly investigated. Therefore, the purpose of this study was to investigate the effects of 17 beta-estradiol, estrone, and 17 alpha-estradiol at three different doses on two different tasks: hippocampus-dependent contextual fear conditioning and hippocampus-independent cued fear conditioning. Adult ovariectomized female rats were injected with one of the estrogens at one of the three doses 30 mins before conditioning to assess the rapid effects of these estrogens on acquisition. Twenty-four hours later memory for the context was examined and 1 h later memory for the cue (tone) was assessed. Levels of synaptophysin were examined in the dorsal hippocampus of rats to identify a potential synaptic correlate of hormonal effects on contextual fear conditioning. Low 17 beta-estradiol and 17 alpha-estradiol enhanced, whereas high 17 beta-estradiol and 17 alpha-estradiol impaired, contextual fear conditioning. Only the middle dose of estrone severely impaired contextual fear conditioning. Estrogens did not alter performance in the hippocampus-independent cued task. Synaptophysin expression was increased by estrone (at a middle and high dose) and 17 beta-estradiol (at a middle dose) in the CA3 region of the hippocampus and was not correlated with cognition. The results of this study indicate that estradiol can positively or negatively influence hippocampus-dependent learning and memory, whereas estrone impairs hippocampus-dependent learning and memory in a dose-dependent manner. These results have important therapeutic implications, as estrone, a main component of a widely used hormone replacement therapy, was shown to have either a negative effect or no effect on learning and memory. It may be possible to use 17 alpha-estradiol and lower doses of estrogens as potential alternatives in hormone replacement therapies. Neuropsychopharmacology (2010) 35, 547-559; doi: 10.1038/npp.2009.161; published online 21 October 2009