Elsevier

Neuroscience

Volume 202, 27 January 2012, Pages 131-146
Neuroscience

Cellular and Molecular Neuroscience
Research Paper
Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation

https://doi.org/10.1016/j.neuroscience.2011.11.035Get rights and content

Abstract

Estradiol affects hippocampal-dependent spatial memory and underlying structural and electrical synaptic plasticity in female mice and rats. Using estrogen receptor (ER) alpha and beta knockout mice and wild-type littermates, we investigated the role of ERs in estradiol effects on multiple pathways important for hippocampal plasticity and learning. Six hours of estradiol administration increased immunoreactivity for phosphorylated Akt throughout the hippocampal formation, whereas 48 h of estradiol increased immunoreactivity for phosphorylated TrkB receptor. Estradiol effects on phosphorylated Akt and TrkB immunoreactivities were abolished in ER alpha and ER beta knockout mice. Estradiol also had distinct effects on immunoreactivity for post-synaptic density 95 (PSD-95) and brain derived-neurotrophic factor (BDNF) mRNA in ER alpha and beta knockout mice. Thus, estradiol acts through both ERs alpha and beta in several subregions of the hippocampal formation. The different effects of estradiol at 6 and 48 h indicate that several mechanisms of estrogen receptor signaling contribute to this female hormone's influence on hippocampal synaptic plasticity. By further delineating these mechanisms, we will better understand and predict the effects of endogenous and exogenous ovarian steroids on mood, cognition, and other hippocampal-dependent behaviors.

Highlights

▶We examined the effect of estradiol treatment on Akt and BDNF signaling in the mouse hippocampus. ▶Estradiol treatment for 6 h increased pAkt immunoreactivity, whereas estradiol treatment for 48 h increased pTrkB immunoreactivity. ▶Estradiol effects were all blocked by knockout of estrogen receptor beta. ▶Estradiol effects on Akt and TrkB were blocked by knockout of estrogen receptor alpha.

Section snippets

Animals

All animal procedures were approved by the Institutional Animal Care and Use Committee of The Rockefeller University and the University of Tsukuba and were in accordance with the NIH Guide for the Care and Use of Laboratory Animals. Mice were housed at the University of Tsukuba on a 12-h light/dark cycle with food and water available ad libitum for the duration of the studies. Mice were adult females between the ages of 9 and 20 weeks, with ages counterbalanced across groups.

AERKO and BERKO

Estradiol treatment for 6 h increases pAkt-ir via ERs alpha and beta

Ovariectomized wild-type AERKO and BERKO littermates (hereafter referred to as “wild-type mice”) were treated with 5 μg estradiol benzoate or oil vehicle for 6 or 48 h, and pAkt-ir was assayed using immunocytochemistry and densitometry (Fig. 2). pAkt-ir was found in areas containing neuropil in the mouse hippocampal formation, with the densest labeling in the CA1 subregion (Fig. 2A, B). Two-way ANOVA showed a significant overall effect of hippocampal subregion for both 6- and 48-h time points (F

Discussion

In humans, the hippocampal formation has been implicated in changes in mood and memory associated with fluctuations in circulating estrogen, across the menstrual cycle and after estrogenic therapies for breast cancer (Eberling et al., 2004, Protopopescu et al., 2008a, Protopopescu et al., 2008b). Dissecting how estrogens act in this brain region, through which receptors and modes of signaling, will enable us to explain and predict the effects of natural and pharmacologic estrogens in different

Acknowledgments

The authors acknowledge Dr. Diane Lane at Weill Cornell Medical College for valuable advice on statistical analysis. Support for this work was provided by NIH grants MH082528 and GM07739 (J.L.S.), DA08259 (T.A.M.), DK07313 (E.M.W.), NS007080 and AG016765 (B.S.M.), and JSPS grants 17052001 and 20022005 (S.O.).

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