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

Nat Neurosci. 2008 Mar;11(3):334-43. doi: 10.1038/nn2057. Epub 2008 Feb 24.

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 (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Estradiol / metabolism
  • Estradiol / pharmacology
  • Estrogen Receptor beta / agonists
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism*
  • Estrogens / agonists
  • Estrogens / metabolism*
  • Estrogens / pharmacology
  • Female
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory / drug effects
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Organ Culture Techniques
  • Ovariectomy
  • Phosphorylation / drug effects
  • Rats
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Estrogen Receptor beta
  • Estrogens
  • Estradiol