Article abstract
Nature Neuroscience 11, 334 - 343 (2008)
Published online: 24 February 2008 | doi:10.1038/nn2057
Activation of estrogen receptor-
regulates hippocampal synaptic plasticity and improves memory
Feng Liu1,6, Mark Day2,6, Luis C Muñiz1, Daniel Bitran3, Robert Arias1, Raquel Revilla-Sanchez4, Steve Grauer1, Guoming Zhang1, Cody Kelley1, Virginia Pulito1, Amy Sung1, Ronald F Mervis5, Rachel Navarra1, Warren D Hirst1, Peter H Reinhart1, Karen L Marquis1, Stephen J Moss4, Menelas N Pangalos1 & Nicholas J Brandon1
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 (ER
) and beta (ER
) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ER. Selective ER agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ER knockout mice. In hippocampal slices, ER activation enhanced long-term potentiation, an effect that was absent in slices from ER knockout mice. ER activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ER agonist, but not an ER agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ER can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.
- Wyeth Research, Discovery Neuroscience, 865 Ridge Road, Monmouth Junction, New Jersey 08852, USA.
- Wyeth Research, Discovery Translational Medicine, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA.
- Department of Psychology, College of the Holy Cross, One College Street, Worcester, Massachusetts 01610, USA.
- Department of Neuroscience, University of Pennsylvania, 145 Johnson Pavilion, Philadelphia, Pennsylvania 19104, USA.
- Neurostructural Research Labs, Inc., Center of Excellence in Aging and Brain Repair, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, Florida 33637, USA.
- These authors contributed equally to this work.
Correspondence to: Feng Liu1,6 e-mail: liuf2@wyeth.com
Correspondence to: Mark Day2,6 e-mail: daym1@wyeth.com
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