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The 17 and 17ß Isomers of Estradiol Both Induce Rapid Spine Synapse Formation in the CA1 Hippocampal Subfield of Ovariectomized Female Rats

Center for Neural Recovery and Rehabilitation Research (N.J.M.), Helen Hayes Hospital, New York, New York 10993; Departments of Obstetrics, Gynecology and Reproductive Sciences (T.H., C.L.) and Neurobiology (C.L.), Yale University School of Medicine, New Haven, Connecticut; Department of Psychology (V.N.L.), Hunter College of City University of New York, New York, New York; and Laboratory of Molecular Neurobiology (T.H.), Biological Research Center, Hungarian Academy of Sciences, H6726 Szeged, Hungary

Address all correspondence and requests for reprints to: Neil J. MacLusky, Ph.D., Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, West Haverstraw, New York, New York 10993. E-mail: macluskyn{at}helenhayeshosp.org.

Previous studies have demonstrated that estradiol-17ß and estradiol-17 both induce short-latency effects on spatial memory in rats, estradiol-17 being at least as potent as its 17ß 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-17ß. The PSSD response was significantly greater (44% above control) 30 min after estradiol-17ß injection and was markedly dose dependent; a 3-fold lower estradiol-17ß dose (15 µg/kg) did not significantly affect CA1 PSSD at either 30 min or 4.5 h. Estradiol-17 was a more potent inducer of PSSD than estradiol-17ß. Dose-response analysis determined an ED₅₀ for the effect of estradiol-17 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-17 than to estradiol-17ß, 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-17 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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