Previous studies have demonstrated that estradiol-17β and estradiol-17α both induce short-latency effects on spatial memory in rats, estradiol-17α being at least as potent as its 17β isomer. To determine whether the mechanisms underlying these behavioral responses might include effects on hippocampal synaptic plasticity, CA1 pyramidal spine synapse density (PSSD) was measured in ovariectomized rats within the first few hours after sc estrogen injection. PSSD increased markedly (by 24%) 4.5 h after the administration of 45 μg/kg estradiol-17β. The PSSD response was significantly greater (44% above control) 30 min after estradiol-17β injection and was markedly dose dependent; a 3-fold lower estradiol-17β dose (15 μg/kg) did not significantly affect CA1 PSSD at either 30 min or 4.5 h. Estradiol-17α was a more potent inducer of PSSD than estradiol-17β. Dose-response analysis determined an ED50 for the effect of estradiol-17α on PSSD of 8.92 ± 1.99 μg/kg, with a maximal response at 15 μg/kg. These results demonstrate that high doses of estradiol induce rapid changes in CA1 PSSD. CA1 spine synapse formation appears to be more sensitive to estradiol-17α than to estradiol-17β, paralleling previous data on the effects of these two steroids on spatial memory. Rapid remodeling of hippocampal synaptic connections may thus contribute to the enhancement of spatial mnemonic processing observed within the first few hours after estrogen treatment. The potency of estradiol-17α suggests that hormone replacement therapy using this steroid might be useful clinically in ameliorating the impact of low endogenous estrogen production on the development and progression of neurodegenerative disorders involving the hippocampus.
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