Progesterone prevents estradiol-induced dendritic spine formation in cultured hippocampal neurons

Neuroendocrinology. 2000 Sep;72(3):133-43. doi: 10.1159/000054580.

Abstract

Estradiol has been shown to cause an increase in dendritic spine density in cultured hippocampal neurons, an effect mediated by downregulation of brain-derived neurotrophic factor (BDNF) and glutamic acid decarboxylase (GAD), and the subsequent phosphorylation of cAMP response element binding protein (CREB) in response to enhanced activity levels. Interestingly, progesterone was shown to counteract the effects of estradiol on dendritic spine density in vivo and in vitro. The present study examined how progesterone may act to block the effects of estradiol in the molecular cascade of cellular events leading to formation of dendritic spines. Progesterone did not affect the estradiol-induced downregulation of BDNF or GAD, but it did block the effect of estradiol on CREB phosphorylation. The latter effects of progesterone on the pCREB response and spine formation were reversed by indomethacin, which prevents the conversion of progesterone to the neurosteroid tetrahydroprogesterone (THP). We therefore examined if the progesterone effects were caused by its active metabolite THP. Progesterone treatment caused a 60-fold increase in THP in the culture medium. THP itself enhanced spontaneous GABAergic activity in patch-clamped cultured neurons. Finally, THP blocked the estradiol-induced increase in spine density. These results suggest that progesterone, through conversion to THP, blocks the effects of estradiol on dendritic spines not via a direct nuclear receptor interaction but by counteracting the enhanced excitability produced by estradiol in the cultured network.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Size / drug effects
  • Cell Size / physiology
  • Cells, Cultured / cytology
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dendrites / drug effects*
  • Dendrites / metabolism*
  • Dendrites / ultrastructure
  • Drug Interactions / physiology
  • Estradiol / metabolism*
  • Estradiol / pharmacology
  • Fetus
  • Glutamate Decarboxylase / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism*
  • Hippocampus / ultrastructure
  • Indomethacin / pharmacology
  • Microscopy, Electron
  • Mifepristone / pharmacology
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Patch-Clamp Techniques
  • Pregnanolone / analogs & derivatives
  • Pregnanolone / metabolism
  • Pregnanolone / pharmacology
  • Progesterone / analogs & derivatives
  • Progesterone / metabolism*
  • Progesterone / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Mifepristone
  • Progesterone
  • Estradiol
  • gamma-Aminobutyric Acid
  • Pregnanolone
  • Glutamate Decarboxylase
  • Indomethacin