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Activation of estrogen receptor-β regulates hippocampal synaptic plasticity and improves memory

Nature Neuroscience volume 11, pages 334–343 (2008)Cite this article

Abstract

Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERα) and beta (ERβ) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERβ. Selective ERβ agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERβ knockout mice. In hippocampal slices, ERβ activation enhanced long-term potentiation, an effect that was absent in slices from ERβ knockout mice. ERβ activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERβ agonist, but not an ERα agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERβ can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.

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Figure 1: Hippocampus-dependent spatial memory is enhanced by estradiol in OVX WT and Esr1−/− mice but not in OVX Esr2−/− mice.
Figure 2: ERβ activation induces estrogen receptor translocation to the nucleus and increases pCREB level in rats and βWT mice, but not in Esr2−/− mice.
Figure 3: ERβ activation increases AMPAR GluR1 and PSD-95 expression levels in rat and mouse hippocampus.
Figure 4: ERβ activation increases GluR1 and synaptophysin expression in CA1 and dentate gyrus regions.
Figure 5: ERβ activation increases the surface expression of GluR1 and phosphorylation at residue Ser845.
Figure 6: ERβ activation potentiates LTP induced in area CA1 by theta burst stimulation (TBS) of the Schaffer collateral pathway in hippocampal slices from WT mice but not Esr2−/−.
Figure 7: ERβ activation increases dendritic branching and density of mushroom spines in the hippocampus.
Figure 8: The ERβ agonist WAY-200070, but not the ERα agonist PPT, improves performance on a hippocampus-dependent radial arm maze task.

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Acknowledgements

We thank T. Comery, M. Hayoun and M. Sharma for their technical assistance. We are also grateful to A. Randall, E. Trybulski and H. Harris for their critical comments on this manuscript. S.J.M. is supported by US National Institutes of Health/National Institute of Neurological Disorders and Stroke grants NS 046478, 048045, 051195 056359, P01NS054900 and the UK Medical Research Council.

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  1. Feng Liu and Mark Day: These authors contributed equally to this work.

Authors and Affiliations

  1. Wyeth Research, Discovery Neuroscience, 865 Ridge Road, Monmouth Junction, 08852, New Jersey, USA

    Feng Liu, Luis C Muñiz, Robert Arias, Steve Grauer, Guoming Zhang, Cody Kelley, Virginia Pulito, Amy Sung, Rachel Navarra, Warren D Hirst, Peter H Reinhart, Karen L Marquis, Menelas N Pangalos & Nicholas J Brandon

  2. Wyeth Research, Discovery Translational Medicine, 500 Arcola Road, Collegeville, 19426, Pennsylvania, USA

    Mark Day

  3. Department of Psychology, College of the Holy Cross, One College Street, Worcester, 01610, Massachusetts, USA

    Daniel Bitran

  4. Department of Neuroscience, University of Pennsylvania, 145 Johnson Pavilion, Philadelphia, 19104, Pennsylvania, USA

    Raquel Revilla-Sanchez & Stephen J Moss

  5. Neurostructural Research Labs, Inc., Center of Excellence in Aging and Brain Repair, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, 33637, Florida, USA

    Ronald F Mervis

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Liu, F., Day, M., Muñiz, L. et al. Activation of estrogen receptor-β regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci 11, 334–343 (2008). https://doi.org/10.1038/nn2057

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