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HIPPOCAMPAL NEURONS: ESTROGEN SYNTHESIS AND REGULATION OF ESTROGEN RECEPTOR ISOFORMS AND .
Prange-Kiel, Janine1, Wehrenberg, Uwe1, Jarry, Hubertus2, Zhou, Lepu1, Rune, Gabriele1, 1 2
ABSTRACT- In the hippocampus the protective function of estrogen and its influence on neuroplasticity is frequently discussed. Since the existence of steroidogenic enzymes (i.e. StAR, aromatase) in hippocampal neurons has been shown, we studied estrogen synsthesis in hippocampal neurons. For the estrogen receptor (ER), the mediator of estrogen action, two isoforms ( and ) exist and both have been shown to be expressed in hippocampal neurons. For the reproduction system it is known, that the expression of the receptors is regulated by their own ligand. Therefore, we studied ligand-induced receptor expression in hippocampal neurons. Hippocampal cell cultures of 10 weeks old female rats containing more than 80 % neurons (MAP-2 positive cells) were used as an in vitro model. In order to examine the capability of the cells to synthesize estrogens the serum- and estradiol-free medium was supplemented with letrozol (10-9 M), an aromatase inhibitor, for 7 days. Estradiol in the conditioned medium was quantified by RIA. To study the influence of estradiol on the expression of ER and , culture medium was supplemented with estradiol (10-7 M) or letrozol (10-9 M) for 7 days. The expression of ER and on mRNA level was analyzed by semiquantitative Taq-Man-RT-PCR. The amount of ER on protein level was measured by immunocytochemistry and subsequent semiquantitative digital image analysis. Estrogen production in letrozol treated hippocampal cells was on control level (unconditioned medium), whereas the estrogen level of non-treated cells was significantly above control. Estrogen treatment resulted in a significant increase of ER on mRNA and protein level, while ER was slightly down regulated. In contrast letrozol induced a significant decrease of ER but an increase in ER. Here we demonstrate for the first time that hippocampal neurons produce estrogen. This synthesis can be inhibited by inhibition of aromatase. Furthermore, estrogen regulates ER receptor isoforms in a differential way: ER is up regulated by its ligand and down regulated by letrozol, that inhibits the cellular synthesis of estradiol. In contrast ER is down regulated by its ligand, and inhibition of internal estrogen synthesis results in a up regulation of this receptor isoform.
KEY WORDS: estrogen synthesis, estrogen receptor, hippocampus, aromatase inhibitor
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