Ontogeny of Neuroendocrine Interactions

Progesterone Prevents Estradiol-Induced Dendritic Spine Formation in Cultured Hippocampal Neurons
Diane D. Murphy^a, Menahem Segal<sup>b

a</sup>NINDS, NIH, Bethesda, Md., USA;
^bDepartment of Neurobiology, The Weizmann Institute, Rehovot, Israel

Address of Corresponding Author

Neuroendocrinology 2000;72:133-143 (DOI: 10.1159/000054580)

  Key Words

• Gonadal steroids
• Hippocampus
• Dendritic spines
• Ontogeny
• Nerve growth factors
• Glutamic acid decarboxylase
• Cyclic AMP
• GABA
• Electrophysiology
• CREB

  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.

Copyright © 2000 S. Karger AG, Basel

  Author Contacts

M. Segal
Department of Neurobiology, The Weizmann Institute
Rehovot 76100 (Israel)
Tel. +972 8 934 2553, Fax +972 8 934 4140
E-Mail menahem.segal@weizmann.ac.il

  Article Information

Received: Received: December 28, 1999
Accepted after revision: May 23, 2000
Number of Print Pages : 11
Number of Figures : 7, Number of Tables : 1, Number of References : 32