Estradiol suppresses glutamatergic transmission to gonadotropin-releasing hormone neurons in a model of negative feedback in mice

Biol Reprod. 2009 Jun;80(6):1128-35. doi: 10.1095/biolreprod.108.075077. Epub 2009 Jan 28.


A surge of gonadotropin-releasing hormone (GnRH) release from the brain triggers the luteinizing hormone (LH) surge that causes ovulation. The GnRH surge is initiated by a switch in estradiol action from negative to positive feedback. Estradiol signals critical for the surge are likely transmitted to GnRH neurons at least in part via estradiol-sensitive afferents. Using an ovariectomized estradiol-treated (OVX+E) mouse model that exhibits daily LH surges, we examined changes in glutamate transmission to GnRH neurons during negative feedback and positive feedback. Spontaneous glutamatergic excitatory postsynaptic currents (EPSCs) mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate receptors (AMPA/KA Rs) or N-methyl-D-aspartate receptors (NMDARs) were recorded in GnRH neurons from OVX+E and OVX mice. There were no diurnal changes in the percentage of GnRH neurons from OVX mice exhibiting EPSCs. In cells from OVX+E mice, the profile of AMPA/KA R-mediated and NMDAR-mediated EPSCs showed changes dependent on time of day. Comparison of AMPA/KA R-mediated EPSC frequency in OVX+E and OVX cells showed that estradiol suppressed transmission during negative feedback but had no effect during positive feedback. Tetrodotoxin treatment to block action potential firing did not affect AMPA/KA R-mediated EPSC frequency in OVX cells during negative feedback or in OVX+E cells during positive feedback, suggesting that estradiol-induced suppression of glutamate transmission may be primarily due to activity-independent changes. The diurnal removal of estradiol-induced suppression of AMPA/KA R-mediated glutamate transmission to GnRH neurons during positive feedback suggests that the primary role for estradiol-induced changes in glutamate transmission may be in mediating negative feedback.

Publication types

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

MeSH terms

  • Animals
  • Circadian Rhythm
  • Estradiol / metabolism*
  • Excitatory Postsynaptic Potentials
  • Feedback, Physiological*
  • Female
  • Glutamic Acid / metabolism*
  • Gonadotropin-Releasing Hormone / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Ovariectomy
  • Receptors, Kainic Acid / metabolism
  • Synaptic Transmission*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism


  • Receptors, Kainic Acid
  • Gonadotropin-Releasing Hormone
  • Glutamic Acid
  • Estradiol
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid