Regulation of the mouse medial prefrontal cortical synapses by endogenous estradiol

Neuropsychopharmacology. 2014 Aug;39(9):2086-94. doi: 10.1038/npp.2014.56. Epub 2014 Mar 10.


Recent studies suggest that low endogenous estradiol might be a susceptibility factor for anxiety and trauma-related disorders in women. Consistently, fear extinction, a form of inhibitory learning critical for the management of anxiety symptoms, is positively correlated with endogenous estradiol levels. To understand the synaptic basis of the effect of endogenous estradiol on fear extinction, we studied glutamatergic transmission and plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region crucial for the regulation of fear extinction. Diestrus mice (low estradiol) exhibited a higher basal glutamatergic transmission compared with proestrus mice (high estradiol). Synaptic plasticity was also regulated by endogenous estradiol, which favored synaptic potentiation in a GluN2B-dependent manner. Activation of estrogen receptor β (ERβ) but not ERα rescued synaptic potentiation in diestrus mice by enhancing GluN2B-mediated NMDA receptor transmission. Our results suggest that both endogenous estradiol and ERβ activation facilitate the ability of the IL-mPFC synapses to undergo potentiation, a mechanism necessary for the regulation of fear extinction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Diestrus / physiology
  • Estradiol / metabolism*
  • Estrogen Receptor alpha / agonists
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / agonists
  • Estrogen Receptor beta / metabolism
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Fear / drug effects
  • Fear / physiology*
  • Female
  • Glutamic Acid / metabolism
  • Male
  • Mice, Inbred C57BL
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology*
  • Proestrus / physiology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / drug effects
  • Synapses / physiology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Estradiol