Proliferation and apoptosis of hippocampal granule cells require local oestrogen synthesis

Abstract

Ovarian oestrogens have been demonstrated to influence neurogenesis in the dentate gyrus. As considerable amounts of oestrogens are synthesized in hippocampal neurones, we focused on the role of hippocampus-derived estradiol on proliferation and apoptosis of granule cells in vitro. We used hippocampal dispersion cultures, which allowed for cultivation of the cells under steroid- and serum-free conditions and monitoring of oestrogen synthesis. To address the influence of hippocampus-derived estradiol on neurogenesis, we inhibited oestrogen synthesis by treatment of hippocampal cell cultures with letrozole, a specific aromatase inhibitor. Alternatively, we used siRNA against steroidogenic acute regulatory protein (StAR). The number of proliferative cells decreased whereas the number of apoptotic cells increased dose-dependently, in response to reduced estradiol release into the medium after treatment with letrozole. This also held true for siRNA against StAR transfected cell cultures. Application of estradiol to the medium had no effect on proliferation and apoptosis whereas the anti-proliferative and pro-apoptotic effects of StAR knock-down and letrozole treatment were restored by treatment of the cultures with estradiol. Our findings suggest that neurogenesis and apoptosis in the hippocampus require a defined range of estradiol concentrations that is physiologically provided by hippocampal cells but not by gonads.