Autocrine loops as a regulatory mechanism of estrogen action in rat hippocampus

Abstract

In a previous study we have shown that synaptic plasticity in rat hippocampus is regulated by hippocampus-derived estradiol in a paracrine manner. Here, we ask whether this paracrine regulation is related to specific hippocampal regions, suggesting autocrine loops. To this end we studied the expression of stereogenic acute regulatory protein (StAR) and aromatase in tissue sections. Immunohistochemistry followed by semiquantitative image analysis revealed a three- fold higher expression of StAR and aromatase in neurons of the CA3 than of the CA1 region and in granule cells. Next, we reduced hippocampal estrogen synthesis in vitro with letrozole, an aromatase inhibitor. Letrozole treatment resulted in a dose-dependent decrease of 17β-estradiol in the medium of hippcampal slice cultures and in a dose-dependent downregulation of synaptic protein expression in hippocampal dispersion cultures. In hippocampal slice cultures spinophilin and synaptophysin are downregulated in a region-specific manner. The downregulation of both proteins was significantly higher in CA1 neurons and in granule cells, than in the CA3 region of the same slice. Our results strongly suggest independent autocrine loops in the regulation of synaptic proteins by hippocampus-derived estradiol and point to distinct functions of locally synthesized estradiol in closely defined hippocampal areas. Support contributed by the DFG.