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The Journal of Neuroscience, July 2, 2003, 23(13):5771-5777
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Estrogen Receptor  Mediates Rapid Estrogen Actions on Gonadotropin-Releasing Hormone Neurons In Vivo
István M. Ábrahám,1
Seong-Kyu Han,1
Martin G. Todman,1
Kenneth S. Korach,2 and
Allan E. Herbison1,3
1Laboratory of Neuroendocrinology, The Babraham
Institute, Cambridge CB2 4AT, United Kingdom,
2Receptor Biology Section, Laboratory of Reproductive
and Developmental Toxicology, National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina 27709, and
3Centre for Neuroendocrinology, Department of
Physiology, University of Otago School of Medical Sciences, Dunedin, New
Zealand
The gonadal steroid estrogen exerts an important modulatory influence on
the activity of multiple neuronal networks. In addition to classical genomic
mechanisms of action, estrogen also exerts poorly understood rapid, nongenomic
effects on neurons. To examine whether estrogen may exert rapid actions on
intracellular signaling within gonadotropin-releasing hormone (GnRH) neurons
in vivo,we examined the phosphorylation status of cAMP response
element-binding protein (CREB) in these cells after the administration of
17- -estradiol to ovariectomized (OVX) mice. The percentage of GnRH
neurons expressing phosphorylated CREB was increased more than sixfold
(p < 0.05) in a time- and dose-dependent manner by estrogen, with
the increase first observed 15 min after estrogen administration. A series of
in vitro studies demonstrated that estrogen acted directly on native
GnRH neurons to phosphorylate CREB, but that estrogen conjugated to bovine
serum albumin was without effect. The role of classical estrogen receptors
(ERs) was evaluated using ER knock-out mice in vivo. The effect of
estrogen on CREB phosphorylation in GnRH neurons was normal in ER
knock-out mice but completely absent in ER knock-out mice. Finally,
studies in intact female mice revealed levels of CREB phosphorylation within
GnRH neurons that were equivalent to those of estrogen-treated OVX mice. These
observations demonstrate that ER mediates the rapid, direct effects of
estrogen on the GnRH neuronal phenotype, and that these actions persist under
physiological conditions. They also provide the first evidence for a role of
ER in nongenomic estrogen signaling within the brain in
vivo.
Key words: CREB; estrogen; estrogen receptor ; GnRH; LHRH; nongenomic; rapid; transgenics
Received Feb. 20, 2003;
revised Apr. 16, 2003;
accepted Apr. 22, 2003.
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