Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation

Neuroscience. 2012 Jan 27;202:131-46. doi: 10.1016/j.neuroscience.2011.11.035. Epub 2011 Nov 23.


Estradiol affects hippocampal-dependent spatial memory and underlying structural and electrical synaptic plasticity in female mice and rats. Using estrogen receptor (ER) alpha and beta knockout mice and wild-type littermates, we investigated the role of ERs in estradiol effects on multiple pathways important for hippocampal plasticity and learning. Six hours of estradiol administration increased immunoreactivity for phosphorylated Akt throughout the hippocampal formation, whereas 48 h of estradiol increased immunoreactivity for phosphorylated TrkB receptor. Estradiol effects on phosphorylated Akt and TrkB immunoreactivities were abolished in ER alpha and ER beta knockout mice. Estradiol also had distinct effects on immunoreactivity for post-synaptic density 95 (PSD-95) and brain derived-neurotrophic factor (BDNF) mRNA in ER alpha and beta knockout mice. Thus, estradiol acts through both ERs alpha and beta in several subregions of the hippocampal formation. The different effects of estradiol at 6 and 48 h indicate that several mechanisms of estrogen receptor signaling contribute to this female hormone's influence on hippocampal synaptic plasticity. By further delineating these mechanisms, we will better understand and predict the effects of endogenous and exogenous ovarian steroids on mood, cognition, and other hippocampal-dependent behaviors.

Publication types

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

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / biosynthesis
  • Brain-Derived Neurotrophic Factor / genetics
  • Data Interpretation, Statistical
  • Densitometry
  • Disks Large Homolog 4 Protein
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / drug effects*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor beta / drug effects*
  • Estrogen Receptor beta / genetics
  • Estrous Cycle / drug effects
  • Estrous Cycle / physiology
  • Female
  • Guanylate Kinases / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Hormone Replacement Therapy
  • Immunohistochemistry
  • In Situ Hybridization
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Pathways / drug effects*
  • Neuronal Plasticity / drug effects*
  • Ovariectomy
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, trkB / biosynthesis
  • Receptor, trkB / genetics
  • Synapses / drug effects*


  • Brain-Derived Neurotrophic Factor
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Membrane Proteins
  • Estradiol
  • Receptor, trkB
  • Proto-Oncogene Proteins c-akt
  • Guanylate Kinases