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Classical Estrogen Receptor Signaling Mediates Negative and Positive Feedback on Gonadotropin-Releasing Hormone Neuron Firing

Neuroscience Graduate Program (C.A.C., S.M.M.), Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908; and Division of Endocrinology, Metabolism, and Molecular Medicine (C.G.-K., J.L.J.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Suzanne M. Moenter, P.O. Box 800578, University of Virginia, Charlottesville, Virginia 22908. E-mail: moenter{at}virginia.edu.

During the female reproductive cycle, the neuroendocrine action of estradiol switches from negative feedback to positive feedback to initiate the preovulatory GnRH and subsequent LH surges. Estrogen receptor- (ER) is required for both estradiol negative and positive feedback regulation of LH. ER may signal through estrogen response elements (EREs) in DNA and/or via ERE-independent pathways. Previously, a knock-in mutant allele (ER^–/AA) that selectively restores ERE-independent signaling onto the ER^–/– background was shown to confer partial negative but not positive estradiol feedback on serum LH. The current study investigated the roles of the ERE-dependent and ERE-independent ER pathways for estradiol feedback at the level of GnRH neuron firing activity. The above ER genetic models were crossed with GnRH-green fluorescent protein mice to enable identification of GnRH neurons in brain slices. Targeted extracellular recordings were used to monitor GnRH neuron firing activity using an ovariectomized, estradiol-treated mouse model that exhibits diurnal switches between negative and positive feedback. In wild-type mice, GnRH neuron firing decreased in response to estradiol during negative feedback and increased during positive feedback. In contrast, both positive and negative responses to estradiol were absent in GnRH neurons from ER^–/– and ER^–/AA mice. ERE-dependent signaling is thus required to increase GnRH neuron firing to generate a GnRH/LH surge. Furthermore, ERE-dependent and -independent ER signaling pathways both appear necessary to mediate estradiol negative feedback on serum LH levels, suggesting central and pituitary estradiol feedback may use different combinations of ER signaling pathways.

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