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

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-alpha (ER alpha) is required for both estradiol negative and positive feedback regulation of LH. ER alpha may signal through estrogen response elements (EREs) in DNA and/or via ERE-independent pathways. Previously, a knock-in mutant allele (ER alpha(-/AA)) that selectively restores ERE-independent signaling onto the ER alpha(-/-) 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 alpha pathways for estradiol feedback at the level of GnRH neuron firing activity. The above ER alpha 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 alpha(-/-) and ER alpha(-/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 alpha 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 alpha signaling pathways. (Endocrinology 149: 5328-5334, 2008)