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

Estradiol has been shown to cause an increase in dendritic spine density in cultured hippocampal neurons, an effect mediated by downregulation of brai n-derived neurotrophic factor (BDNF) and glutamic acid decarboxylase (GAD), and the subsequent phosphorylation of cAMP response element binding protei n (CREB) in response to enhanced activity levels. Interestingly, progestero ne was shown to counteract the effects of estradiol on dendritic spine dens ity in vivo and in vitro. The present study examined how progesterone may a ct to block the effects of estradiol in the molecular cascade of cellular e vents 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 progeste rone on the pCREB response and spine formation were reversed by indomethaci n, which prevents the conversion of progesterone to the neurosteroid tetrah ydroprogesterone (THP). We therefore examined if the progesterone effects w ere caused by its active metabolite THP. Progesterone treatment caused a 60 -fold increase in THP in the cu Itu re medium. THP itself enhanced spontane ous GABAergic activity in patch-clamped cultured neurons. Finally, THP bloc ked the estradiol-induced increase in spine density. These results suggest that progesterone, through conversion to THP, blocks the effects of estradi ol on dendritic spines not via a direct nuclear receptor interaction but by counteracting the enhanced excitability produced by estradiol in the cultu red network. Copyright (C) 2000 S. Karger AG, Basel.