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Laboratory of Neuroendocrinology (I.M.A., M.G.T., A.E.H.), Babraham Institute, Cambridge CB2 4AT, United Kingdom; Neurobiology Research Group (I.M.A.), Hungarian Academy of Sciences, Eötvös Loránd University, H-1117 Budapest, Hungary; Receptor Biology Section (K.S.K.), Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and Centre for Neuroendocrinology and Department of Physiology (A.E.H.), University of Otago School of Medical Sciences, Dunedin, New Zealand
Address all correspondence and requests for reprints to: Allan E. Herbison, Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, P.O. Box 913, Dunedin, New Zealand. E-mail: allan.herbison{at}stonebow.otago.ac.nz.
Estrogen exerts classical genomic as well as rapid nongenomic actions on neurons. The mechanisms involved in rapid estrogen signaling are poorly defined, and the roles of the classical estrogen receptors (ERs
and ß) are unclear. We examined here the in vivo role of classical ERs in rapid estrogen actions by evaluating the estrogen-induced effects on two major signaling pathways within the brains of
ER-, ßER-, and double
ßER-knockout (ERKO) ovariectomized female mice. Estrogen significantly (P < 0.05) increased the numbers of phospho-cAMP response element binding protein (phospho-CREB)-immunoreactive cells in specific brain regions of wild-type mice in a time-dependent manner beginning within 15 min. In brain areas that express predominantly ERß, this response was absent in ßERKO mice, whereas brain regions that express mostly ER
displayed no change in
ERKO mice. In the medial preoptic nucleus (MPN), an area that expresses both ERs, the estrogen-induced phosphorylation of CREB was normal in both
ERKO and ßERKO mice. However, estrogen had no effect on CREB phosphorylation in the MPN, or any other brain region, in double
ßERKO animals. Estrogen was also found to increase MAPK phosphorylation levels in a rapid (<15 min) manner within the MPN. In contrast to CREB signaling, this effect was lost in either
ERKO or ßERKO mice. These data show that ER
and ERß play region- and pathway-specific roles in rapid estrogen actions throughout the brain. They further indicate an indispensable role for classical ERs in rapid estrogen actions in vivo and highlight the importance of ERs in coordinating both classical and rapid actions of estrogen.
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