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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. Herbison^1,3

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

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Received Feb. 20, 2003; revised Apr. 16, 2003; accepted Apr. 22, 2003.

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