The specificity of estrogenic effects on synaptic plasticity in rat hippocampus

Abstract

In previous studies we have shown that synaptic proteins are downregulated in response to letrozole, which prevents the conversion of testosterone to estradiol. As this enzymatic step is the last one in estrogen synthesis the questions arises whether the results from our letrozole experiments are actually due to a lack of estrogen or are due to increased levels of precursors of estrogen synthesis. Therefore, we treated hippocampal cultures with trilostane, and mevastatin, inhibitors of cholesterol and testosterone synthesis, respectively. To confirm the results we used siRNA against StAR. StAR is a protein which transports cholesterol to the inner mitochondrial membrane where steroidogenesis is started by the activity of the P450 side chain cleavage enzyme. “Rescue“ experiments, where we treated these cultures with cholesterol, testosterone and estrogen together with their corresponding inhibitors confirmed the specificity of estrogen action. In siRNA against StAR transfected cells the downregulation of synaptic proteins could be restored by treatment of the cultures with estradiol but not by treatment with testosterone or cholesterol. Our pharmacological experiments revealed similar results. A “rescue“ could only be achieved with estradiol but not with testosterone and cholesterol. Our data show a high specificity of estrogen on synaptic plasticity. Support contributed by the DFG.