Characterization of aromatase expression in the adult male and female mouse brain. I. Coexistence with oestrogen receptors α and β, and androgen receptors.

Davor Stanić,Sydney Dubois,Malcolm K Horne,Bruce Tonge,Wah Chin Boon,Nicole Rinehart,Hui Kheng Chua,Christine Jasoni

doi:10.1371/journal.pone.0090451

Abstract

Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, including the bed nucleus of the stria terminalis, olfactory tubercle, medial amygdaloid nucleus and medial preoptic area, with the densest distributions of EGFP-positive cell bodies in the bed nucleus and medial amygdala. Differences between male and female mice were apparent, with the density of EGFP-positive cell bodies and fibres being lower in some brain regions of female mice, including the bed nucleus and medial amygdala. EGFP-positive cell bodies in the bed nucleus, lateral septum, medial amygdala and hypothalamus co-expressed oestrogen receptor (ER) α and β, or the androgen receptor (AR), although single-labelled EGFP-positive cells were also identified. Additionally, single-labelled ERα−, ERβ- or AR-positive cell bodies often appeared to be surrounded by EGFP-immunoreactive nerve fibres/terminals. The widespread distribution of EGFP-positive cell bodies and fibres suggests that aromatase signalling is common in the mouse brain, and that locally synthesised brain oestrogens could mediate biological effects by activating pre- and post-synaptic oestrogen α and β receptors, and androgen receptors. The higher number of EGFP-positive cells in male mice may indicate that the autocrine and paracrine effects of oestrogens are more prominent in males than females.

Highlights

It has been known for nearly forty years that oestrogens are produced in the brain by the local aromatisation of testosterone [1], and these locally synthesised oestrogens [2] may modulate neuronal functions and provide neuroprotection
As the last step in oestrogen synthesis is aromatisation and as most oestrogen effects are mediated through oestrogen receptors, attempts have been made to compare the distributions of aromatase and oestrogen receptors in the brain [29,30,31,32]
In the transgenic mouse model developed previously by Wu et al [33], the nuclear LacZ reporting gene was integrated into the aromatase locus and the reporter protein is nuclear b-galactosidase, which identifies aromatase positive cell bodies but not the neurites extending from the soma

Summary

Introduction

It has been known for nearly forty years that oestrogens are produced in the brain by the local aromatisation of testosterone [1], and these locally synthesised oestrogens [2] may modulate neuronal functions and provide neuroprotection (reviewed by [3]). High levels of aromatase activity [6] and its mRNA [6,7,8,9,10] have been detected in the hypothalamus, preoptic nucleus, sexually dimorphic nucleus, bed nucleus of the striata terminalis (BST), hippocampal formation [2] and cerebellum [11]. While regions of the brain expressing aromatase are similar in both sexes, there are important differences in their levels of expression. Aromatase activity is four times higher in the hypothalamus of the postpubertal porcine male than female [12]. Aromatase transcript levels are higher in the male rat amygdala, BST and medial septal nucleus than the corresponding nuclei in females [13,14], these differences are not present in some species, including sheep [15]

Methods

Results

Conclusion