Elsevier

Neurobiology of Aging

Volume 27, Issue 6, June 2006, Pages 880-887
Neurobiology of Aging

Expression of estrogen receptor (ER) α and β in mouse cerebral cortex: Effect of age, sex and gonadal steroids

https://doi.org/10.1016/j.neurobiolaging.2005.04.003Get rights and content

Abstract

Estrogen receptor (ER), which mediates the multiple effects of estrogen in brain, is regulated by several factors including its own ligand. In the present study, we have examined the effect of age, sex and gonadal steroids (estrogen and testosterone) on the level of ERα and ERβ in the cerebral cortex of AKR mice. Adult and old mice of both sexes were divided into four groups: intact, gonadectomized, 17β-estradiol treated and testosterone treated. Western blot analysis showed higher level of ERα and ERβ in the cerebral cortex of adult female than male mice. ERβ level decreased significantly with advancing age in both sexes, whereas 17β-estradiol supplementation decreased ERα level in old male and increased in old female, it also increased ERβ level in old male and adult female. On the other hand, testosterone treatment decreased ERα level significantly in old female and ERβ level in adult female but increased ERβ level in male mice of both ages. Thus, these findings showed that the expression of ERα and ERβ protein is differentially influenced by age, sex and gonadal steroids in the mouse cerebral cortex, suggesting differences in ER-mediated brain functions.

Introduction

Estrogen receptor (ER) is a member of the nuclear receptor superfamily of transcription factors, which also includes receptors for sex steroids, thyroid hormone and retinoids as well as many orphan receptors for which no ligand has been identified [19]. There are two types of ERα and ERβ coded by two separate genes located on different chromosomes. Upon binding to its ligand, both receptors undergo conformational changes leading to the formation of either ERα/ERβ homodimer or heterodimer [12], [18]. ERα and ERβ are implicated in several brain functions such as migration of neurons during embryonic development [55], [56], protection against brain injury [14], [60], [61] and improvement in memory and learning [17], [30], [44], increase in choline acetyl transferase activity [34], growth of synapses [7], [46] and decrease of β amyloid level [32].

The brain exhibits sexual differences in its structure and function throughout the animal kingdom [36]. The wide range of effects associated with brain sexual differentiation represents the result of a complex response cascade, initiated by genes and prolonged by the effects of gonadal hormones. Early exposure to a masculine hormonal milieu results in the development of male specific brain while the absence of such a hormonal milieu shifts the development to a female specific brain. Apart from other changes in the brain, variation in the endogenous hormone level was shown to be responsible for differential distribution and density of androgen receptor (AR) and ER [57] in different regions of the brain during early development [36]. Gonadal steroids regulate ER level in the rat brain around 7–10 days after birth [20], [27], thereafter ER concentration declines rapidly and attains the adult pattern. However, in adult female rat brain, the level of ERα mRNA changes during different estrous phases [49]; thus, suggesting the involvement of sex steroids in the control of ER level beyond the early developmental stages. In contrast to adult animals, circulating gonadal hormone level changes with advancing age [28], [50], [51]. While these changes are abrupt in female, they are slow but steady in male [15]. Such sex-related decline in the level of circulating hormones may modulate ERα and ERβ level differentially in male and female during aging [48], [52].

The in situ and immunohistochemical studies conducted in female rat brain revealed that the number of cells expressing ERα and ERβ mRNA and protein show region specific changes during aging [2], [9], [10], [59]. In the present study, Western blot analysis showed differential effect of age, sex and gonadal steroid hormones on the expression of full length ERα and ERβ protein in the cerebral cortex of AKR mice.

Section snippets

Animals and hormone treatment

AKR mice were maintained in a colony at 25 ± 2 °C with free access to standard mice feed and drinking water. They were exposed to 12-h light:12-h dark schedule. The average life span of AKR mice in our colony is 70 ± 5 weeks. We used AKR mice for our study because of their short life span. Experimental protocols were approved by the animal ethical committee of Banaras Hindu University, Varanasi, India. For each experiment, adult (25 ± 2 weeks) and old (65 ± 5 weeks) male and female mice were divided

Age dependent differences in ERα and ERβ level

To know the effect of age, the levels of ERα and ERβ in adults were compared with those in old (Fig. 1, Fig. 2). The adult level was considered as 100%. ERα level did not change in old. In contrast to ERα, ERβ level decreased significantly in both old male (40%, P < 0.05) and female (75%, P < 0.05).

Sex dependent differences in ERα and ERβ level

To know the effect of sex, the level of ERα and ERβ in adult male was considered as 100%. Western blot analysis (Fig. 1) revealed higher level of ERα protein (162%, P < 0.05) in adult female than adult

Discussion

In the present study, we have examined the effect of age, sex and gonadal sex steroid hormones on the levels of ERα and ERβ in the mice cerebral cortex. The cerebral cortex is a recognized target of gonadal sex steroids. In addition to developmental influences [37], behavioral [8] and biochemical [16] studies suggest that estrogen also stimulates the mature cerebrum [35]. Estrogen exerts potent modulatory effects on multiple neuronal networks. Although it is clear that many of the effects of

Acknowledgements

This work was supported by grants from the Department of Biotechnology (BT/PRO831/HRD/15/87/97 and BT/PR3593/Med/14/468/2004) and Department of Science and Technology, Government of India (SP/SO/B05/99) to M.K.T. P.K.S. is a recipient of Junior Research Fellowship from the University Grants Commission, India.

References (62)

  • V.N. Luine

    Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats

    Exp Neurol

    (1985)
  • M.G. Packard

    Post-training estrogen and memory modulation

    Horm Behav

    (1998)
  • C.E. Roselli et al.

    Aromatase activity in the rat brain: hormonal regulation and sex differences

    J Steroid Biochem Mol Biol

    (1993)
  • C.D. Toran-Allerand

    Estrogen and the brain: beyond ER-α and ER-β

    Exp Gerontol

    (2004)
  • M.E. Wilson et al.

    Age differentially influences estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) gene expression in specific regions of the rat brain

    Mech Ageing Dev

    (2002)
  • P.M. Wise et al.

    Estradiol is a protective factor in the adult and aging brain: understanding of mechanisms derived from in vivo and in vitro studies

    Brain Res Brain Res Rev

    (2001)
  • I.M. Abraham et al.

    Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain

    Endocrinology

    (2004)
  • M.M. Adams et al.

    Estrogen and aging affect the subcellular distribution of estrogen receptor-α in the hippocampus of female rats

    J Neurosci

    (2002)
  • E.T. Alarid et al.

    Thyroid hormone is an inhibitor of estrogen-induced degradation of estrogen receptor-α protein: estrogen-dependent proteolysis is not essential for receptor transactivation function in the pituitary

    Endocrinology

    (2003)
  • R.D. Brinton et al.

    17β-estradiol increases the growth and survival of cultured cortical neurons

    Neurochem Res

    (1997)
  • D.M. Broverman et al.

    Changes in cognitive task performance across the menstrual cycle

    J Comp Physiol Psychol

    (1981)
  • T.R. Chakraborty et al.

    Aging-related changes in ovarian hormones, their receptors, and neuroendocrine function

    Exp Biol Med

    (2004)
  • T.R. Chakraborty et al.

    Stereologic analysis of estrogen receptor alpha (ER alpha) expression in rat hypothalamus and its regulation by aging and estrogen

    J Comp Neurol

    (2003)
  • T.R. Chakraborty et al.

    Age-related changes in estrogen receptor β in rat hypothalamus: a quantitative analysis

    Endocrinology

    (2003)
  • D.B. Dubal et al.

    Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury

    Proc Natl Acad Sci USA

    (2001)
  • H.A. Feldman et al.

    Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study

    J Clin Endocrinol Metab

    (2002)
  • G. Fink et al.

    Estrogen control of central neurotransmission: effect on mood, mental state and memory

    Cell Mol Neurobiol

    (1996)
  • S.C. Hewitt et al.

    Estrogen receptors: structure, mechanisms and function

    Rev Endocr Metab Disord

    (2002)
  • Y. Ikeda et al.

    Sexually dimorphic and estrogen-dependent expression of estrogen receptor β in the ventromedial hypothalamus during rat postnatal development

    Endocrinology

    (2003)
  • M. Jankowski et al.

    Estrogen receptors activate atrial natriuretic peptide in rat heart

    Proc Natl Acad Sci USA

    (2001)
  • E.V. Jensen et al.

    Estrogen–receptor interaction

    Science

    (1973)
  • Cited by (0)

    View full text