Glutamatergic transmission to hypothalamic kisspeptin neurons is differentially regulated by estradiol through estrogen receptor α in adult female mice.
- Luhong Wang1,
- Laura L. Burger1,
- Megan L. Greenwald-Yarnell4,
- Martin G. Myers Jr.1,2,5, and
- Suzanne M. Moenter1,2,3
- 1Departments of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
- 2Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI
- 3Internal Medicine, University of Michigan, Ann Arbor, MI
- 4Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI
- 5Michigan Diabetes Research & Training Center, University of Michigan, Ann Arbor, MI
- Corresponding author: Suzanne M. Moenter, Department of Molecular and Integrative Physiology, University of Michigan, 7725 Med Sci II, 1137 E. Catherine St, Ann Arbor, MI 48109-5622 734-647-1750 (voice), 734-936-8813 (fax) smoenter{at}umich.edu
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Author contributions: L.W., L.L.B., and S.M.M. designed research; L.W. performed research; L.W., L.L.B., and S.M.M. analyzed data; L.W., L.L.B., and S.M.M. wrote the paper; M.L.G.-Y. and M.G.M.J. contributed unpublished reagents/analytic tools.
Abstract
Estradiol feedback regulates gonadotropin-releasing hormone (GnRH) neurons and subsequent luteinizing hormone (LH) release. Estradiol acts through estrogen receptor α (ERα)-expressing afferents of GnRH neurons including kisspeptin neurons in the anteroventral periventricular (AVPV) and arcuate nuclei, providing homeostatic feedback on episodic GnRH/LH release as well as positive feedback to control ovulation. Ionotropic glutamate receptors are important for estradiol feedback but it is not known where they fit in the circuitry. Estradiol negative feedback decreased glutamatergic transmission to AVPV and increased it to arcuate kisspeptin neurons; positive feedback had the opposite effect. Deletion of ERα in kisspeptin cells decreased glutamate transmission to AVPV neurons and markedly increased it to arcuate kisspeptin neurons, which also exhibited increased spontaneous firing rate. KERKO mice had increased LH pulse frequency, indicating loss of negative feedback. These observations indicate ERα in kisspeptin cells is required for appropriate differential regulation of these neurons and neuroendocrine output by estradiol.
SIGNIFICANCE STATEMENT
The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian estradiol regulates the pattern of GnRH (negative feedback) and initiate a surge of release that triggers ovulation (positive feedback). GnRH neurons do not express the estrogen receptor needed for feedback (ERα); kisspeptin neurons in the arcuate and anteroventral periventricular nuclei are postulated to mediate negative and positive feedback, respectively. Here we extend the network through which feedback is mediated by demonstrating that glutamatergic transmission to these kisspeptin populations is differentially regulated during the reproductive cycle and by estradiol. Electrophysiological and in vivo hormone profile experiments on kisspeptin-specific ERα knockout mice demonstrate ERα in kisspeptin cells is required for appropriate differential regulation of these neurons and for neuroendocrine output.
Footnotes
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The authors declare no competing financial interests.
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Supported by National Institute of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development R01 HD41469 to SMM, P50 HD28934 (University of Virginia Assay Core) and National Institute of Diabetes and Digestive and Kidney Diseases R01 DK057768 to MGM. We thank Elizabeth R. Wagenmaker for expert technical assistance, the University of Virginia Center for Research in Reproduction Ligand and Assay Core for conducting hormone measurements and James L. Kenyon, University of Nevada, Reno, for the Excel spreadsheet used to calculate junction potentials.
- Received August 24, 2017.
- Revision received September 28, 2017.
- Accepted October 30, 2017.
- Copyright © 2017 the authors
