Elsevier

Neuropharmacology

Volume 75, December 2013, Pages 262-273
Neuropharmacology

Bidirectional modulatory effect of 17β-estradiol on NMDA receptors via ERα and ERβ in the dentate gyrus of juvenile male rats

https://doi.org/10.1016/j.neuropharm.2013.07.029Get rights and content

Highlights

  • Estradiol (E2) is a neurosteroid synthesized locally in the hippocampus.

  • A low E2 dose potentiates, while a high E2 dose suppresses NMDA receptor activity.

  • ERα agonist reproduces the potentiation effect of the low E2 dose.

  • ERβ agonist reproduces the suppressive effect of the high E2 dose.

  • E2 exerts condition-dependent bidirectional effect on NMDA receptors via ERα and ERβ.

Abstract

The neurosteroid 17β-estradiol (E2) is synthesized by aromatase in both male and female hippocampi and is known to modulate hippocampal synaptic functions. However, as some contradictory findings regarding the modulatory effects of E2 have been reported in the literature, its physiological role and mechanism of action in the hippocampus remain controversial. Our recent study showed that a low E2 dose (1 nM) increased the amplitude of NMDA receptor-mediated EPSCs (NMDAR-EPSCs) and lowered the threshold for the induction of NMDA receptor-dependent long-term potentiation (NMDAR-LTP), while a high E2 dose (7 nM) exerted opposite effects in the dentate gyrus of juvenile male rat hippocampal slices. The present study is a follow-up that explores the underlying mechanism of this bidirectional effect of E2. We found that the ERα agonist PPT reproduced the actions of the low E2 dose on NMDAR-EPSCs and NMDAR-LTP, while the ERβ agonist DPN reproduced the actions of the high E2 dose. Moreover, PPT, but not DPN, restored the decrease in NMDAR-EPSCs induced by the aromatase inhibitor letrozole, suggesting that E2 synthesized constitutively in the hippocampus enhances NMDA receptor function via ERα. The PPT-induced enhancement in NMDAR-EPSCs was mediated by Src family kinase, but was not caused by NR2B modulation. These findings demonstrate that E2 exerts condition-dependent bidirectional effects on NMDA receptor-mediated transmission and, thus, synaptic plasticity via ERα and ERβ in the dentate gyrus of juvenile male rats.

Introduction

The steroid 17β-estradiol (E2), which is a major gonadal steroid hormone in females, is also synthesized in the brains of males. Aromatase, an enzyme that converts testosterone to E2, is expressed in granule cells in the dentate gyrus and pyramidal neurons in the CA1 region of the male rat hippocampus, and the basal concentration of E2 in the hippocampus was shown to be markedly higher than that in the plasma (Kimoto et al., 2001, Hojo et al., 2004).

E2 influences brain functions by slow genomic mechanisms via nuclear estrogen receptors, and by fast non-genomic mechanisms via membrane estrogen receptors (ERα and ERβ) and G-protein-coupled receptors (GPR-30 and ER-X) (Brailoiu et al., 2007, Toran-Allerand et al., 2002, Mukai et al., 2007, Woolley, 2007, Foster, 2012). E2 has been shown to act as a potent modulator of glutamatergic and GABAergic synaptic transmission through genomic or non-genomic mechanisms (Ito et al., 1999, Foy et al., 1999, Bi et al., 2000, Huang and Woolley, 2012, Murphy et al., 1998, Nilsen et al., 2002, Smith and McMahon, 2006, Vedder et al., 2013), and induces morphological changes such as neurite growth or dendritic spine formation in the hippocampus (Murphy et al., 1998, Pozzo-Miller et al., 1999, Mukai et al., 2007, Miñano et al., 2008). Moreover, E2 can influence the performance of learning and memory through these functional and morphological changes in the brain circuits of rodents (Wide et al., 2004, Liu et al., 2008, Barha et al., 2010, Foster, 2012).

Although there is mounting evidence to suggest the modulatory effects of E2 on synaptic functions, and the performance of learning and memory, its physiological roles and mechanisms of action in the brain remain controversial. The major reason for this has been attributed to contradictory results regarding the pharmacological effects of E2 on brain functions in separate studies, which may have resulted from variable E2 actions depending on the experimental conditions such as age, sex, or brain regions of animals, or the applied dose of E2 (Ito et al., 1999, Foy et al., 2004, Wide et al., 2004, Prange-Kiel et al., 2006, Barha et al., 2010).

Our recent study showed that the aromatase inhibitor letrozole acutely decreased the amplitude of NMDA receptor-mediated EPSCs (NMDAR-EPSCs) and suppressed NMDA receptor-dependent long-term potentiation (NMDAR-LTP) in the dentate gyrus of juvenile male rat hippocampal slices, suggesting that E2 constitutively synthesized in the hippocampus contributes to the reinforcement of NMDA receptor-mediated transmission and, thus, facilitates synaptic plasticity (Tanaka and Sokabe, 2012). In addition, we also found that an exogenously applied low dose of E2 (1 nM) acutely increased the amplitude of NMDAR-EPSCs and lowered the threshold for the induction of NMDAR-LTP, while an applied high E2 dose (7 nM) exerted opposite effects in the same experimental conditions (see the Supplementary Data of Tanaka and Sokabe, 2012). This finding suggests that the direction (positive or negative) of E2-induced modulation is changed by E2 levels in the brain. However, detailed mechanisms of the dose-dependent bidirectional (positive or negative) action of E2 have not yet been elucidated. Therefore, we investigated the mechanisms of the bidirectional effect of E2 on NMDA receptors in the dentate gyrus of juvenile male rats.

Section snippets

Animals and housing conditions

Young male and female Wistar rats (3–4 weeks of age) were housed in a light controlled room under a 12-h light–dark cycle starting at AM 9:00 and maintained at a temperature of 25 °C. Animals had free access to food and water. All procedures were carried out in accordance with the guidelines established by the Institute for Laboratory Animal Research of the Medical School of Nagoya University.

Hippocampal slice preparation

Rats were decapitated under deep anesthesia with ethyl ether. The brains were quickly removed and

The ERα agonist PPT potentiated, while the ERβ agonist DPN suppressed NMDA receptor-meditated transmission

Our recent study demonstrated that an exogenously applied low E2 dose (1 nM) acutely increased the amplitude of NMDAR-EPSCs, while a high E2 dose (7 nM) acutely decreased the NMDAR-EPSC amplitude in the dentate gyrus of juvenile male rat hippocampal slices (Tanaka and Sokabe, 2012). We first attempted to identify which subtype of estrogen receptors was responsible for the respective E2 effect. The membrane ERα and ERβ are major estrogen receptors that mediate the acute effects of E2 on

Discussion

Our recent and present studies showed that a low E2 dose (1 nM) or the ERα agonist PPT acutely increased the amplitude of NMDAR-EPSCs and lowered the threshold for the induction of NMDAR-LTP, while a high E2 dose (7 nM) or the ERβ agonist DPN acutely decreased the NMDAR-EPSC amplitude and suppressed NMDAR-LTP in the dentate gyrus of juvenile male rat hippocampal slices. Previous studies showed that 1 nM E2 acutely enhanced the magnitude of LTP in adult male rats by positively modulating NMDA

Conflict of interest

The authors have no conflicts of interest to declare.

Acknowledgments

This work was supported by JSPS KAKENHI Grant Number 24700378.

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