Upregulation of estrogen receptors in the forebrain of aromatase knockout (ArKO) mice

Abstract

Estrogens have numerous reproductive and nonreproductive functions in brain. The actions of estrogens are mediated by estrogen receptors (ERs), and estrogens are believed to down-regulate their own receptors in many tissues. Assuming this to be true, if estrogens are removed there should be an upregulation of ERs. We have developed a mouse model in which estrogen synthesis is completely eliminated by homologous recombination to delete the gene encoding aromatase cytochrome P450 (P450 arom). The P450 arom enzyme catalyzes the synthesis of estrogens from androgens in the brain. The localization and density of ERs was studied in the brains of aromatase knockout (ArKO) and wild type male mice by using immunohistochemistry with a peptide antibody to ERα (ER-21) and computer imaging. In the wild-type animals a high density of ERα was found in a small number of hypothalamic cells; in the medial preoptic area, periventricular, arcuate, and ventromedial nuclei. A low and medium density of ERα was observed in cells of the lateral preoptic area, supraoptic, bed nucleus of the stria terminalis, and in central, medial and anterior cortical amygdaloid nuclei. The number of cells containing ERα-immunoreactivity was significantly increased (244%) in the medial preoptic area of the ArKO mice. In neither wild type nor ArKO animals was immunoreactivity observed in the cerebral cortex or striatum. There was intense ER-immunostaining in the nucleus of neurons in both wild type and ArKO mice. These data indicate that in the absence of estrogens there is as much as a 2-fold increase in the number of cells with ERα-immunoreactivity in certain hypothalamic and limbic regions. Thus, estrogens can down-regulate ERα in brain.