Estrogen receptor β (ERβ) protein levels in neurons depend on estrogen receptor α (ERα) gene expression and on its ligand in a brain region-specific manner

Abstract

Estrogen receptors (ERs) α and β are very similar estrogen-binding proteins, perhaps gene duplication products, which act as ligand-dependent transcription factors. While the estrogenic regulation of ERα has been well documented, little is known about how estrogen regulates ERβ and whether ERα plays a role in the expression and estrogenic regulation of ERβ. In the present study, we examined the effects of gonadectomy and estrogen replacement on ERβ immunoreactivity (ir) in wild-type (WT) and ERα knockout (αERKO) adult male mice in six brain regions, the medial preoptic area (MPOA), the bed nucleus of the stria terminalis (BNST), the paraventricular nucleus (PVN), the ventromedial nucleus of hypothalamus (VMH), the medial amygdala nucleus (MeAMY) and the dorsal raphe nucleus (DRN). Mice were divided into four different treatment groups: gonadally intact, gonadectomized (GDX), GDX+short-term treatment with estrogen (s.c. injection of estradiol benzoate (EB), 5 μg, at 48 h before perfusion) or GDX+long-term treatment with estrogen (implant of an EB pellet, 2.5 μg/day, for 10 days). In intact αERKO mice, the number of ERβ expressing cells was significantly decreased in the MPOA and increased in the BNST, compared to WT mice. Both in the MPOA and BNST, steroid hormone regulation of ERβ protein (an increase by GDX and a decline to intact levels by EB) was found only in WT, not in αERKO mice. In the VMH, GDX significantly increased the number of ERβ ir expressing cells in both genotypes. EB treatment tended to decrease the number of ERβ ir cells in WT mice, whereas EB treatment tended to increase ERβ ir cell counts in αERKO mice. No effects of GDX or EB treatment were found in the DRN and MeAMY regardless of genotype. These results suggest that gonadal steroid hormones may regulate ERβ protein in male mice and ERα may be involved in the expression and regulation of ERβ in a region-specific manner.