• Feng Liu, Mark Day, Luis C Muñiz, Daniel Bitran, Robert Arias, Raquel Revilla-Sanchez, Steve Grauer, Guoming Zhang, Cody Kelley, Virginia Pulito, Amy Sung, Ronald F Mervis, Rachel Navarra, Warren D Hirst, Peter H Reinhart, Karen L Marquis, Stephen J Moss, Menelas N Pangalos, and Nicholas J Brandon.
• Wyeth Research, Discovery Neuroscience, 865 Ridge Road, Monmouth Junction, New Jersey 08852, USA. liuf2@wyeth.com
• Nat. Neurosci. 2008 Mar 1; 11 (3): 334-43.

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

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