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

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 alpha) and beta (ER beta) 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 beta. Selective ER beta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ER beta knockout mice. In hippocampal slices, ER beta activation enhanced long-term potentiation, an effect that was absent in slices from ER beta knockout mice. ER beta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ER beta agonist, but not an ER alpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ER beta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.