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The Journal of Neuroscience, September 17, 2003, 23(24):8578-8585

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Metabolic Regulation of Fertility through Presynaptic and Postsynaptic Signaling to Gonadotropin-Releasing Hormone Neurons

Shannon D. Sullivan, R. Anthony DeFazio, and Suzanne M. Moenter

¹Internal Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908

Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction and are inhibited by negative energy balance. In normal adults, these neurons maintain elevated intracellular chloride so that GABA_A receptor activation is excitatory. We hypothesized that fasting alters homeostatic mechanisms to eliminate excitatory responses to GABA but rejected this hypothesis when brief, local GABA application elicited action currents in GnRH neurons from fed and fasted mice. This response was specific to GABA_A receptors, because glycine elicited no response. We next found that fasting reduced the frequency of spontaneous GABAergic postsynaptic currents (PSCs) and that this was reversed by in vivo treatment with leptin during the fast. In the presence of tetrodotoxin to minimize presynaptic actions, leptin also potentiated the postsynaptic response of these cells to GABA_A receptor activation. Postsynaptic effects of leptin on GABAergic miniature PSCs were eliminated by inhibiting JAK2/3 (Janus kinase), the tyrosine kinase through which leptin receptors signal. In all experiments, elimination of PSCs at E_Cl or by treatment with the GABA_A receptor antagonist bicuculline confirmed that PSCs were specifically mediated by GABA_A receptor chloride channels. These data demonstrate that fasting and leptin act presynaptically and postsynaptically to alter GABAergic drive to GnRH neurons, providing evidence for GABAergic communication of metabolic cues to GnRH neurons, and suggest the possibility for functional leptin receptors on GnRH neurons. They further demonstrate cytokine modulation of the postsynaptic response to GABA in mammals, which may be important to central neural regulation in both healthy and diseased states.

Key words: GnRH; GABA; PSC; leptin; cytokine; fertility

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Received Feb 21, 2003; revised July 21, 2003; accepted July 22, 2003.

This article has been cited by other articles:

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				Q. Gao and T. L. Horvath Cross-talk between estrogen and leptin signaling in the hypothalamus Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E817 - E826. [Abstract] [Full Text] [PDF]

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				Z. Chu and S. M. Moenter Physiologic Regulation of a Tetrodotoxin-Sensitive Sodium Influx That Mediates a Slow Afterdepolarization Potential in Gonadotropin-Releasing Hormone Neurons: Possible Implications for the Central Regulation of Fertility. J. Neurosci., November 15, 2006; 26(46): 11961 - 11973. [Abstract] [Full Text] [PDF]

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				S. M. Moenter and R. A. DeFazio Endogenous {gamma}-Aminobutyric Acid Can Excite Gonadotropin-Releasing Hormone Neurons Endocrinology, December 1, 2005; 146(12): 5374 - 5379. [Abstract] [Full Text] [PDF]

				Z. Chu and S. M. Moenter Endogenous Activation of Metabotropic Glutamate Receptors Modulates GABAergic Transmission to Gonadotropin-Releasing Hormone Neurons and Alters Their Firing Rate: A Possible Local Feedback Circuit J. Neurosci., June 15, 2005; 25(24): 5740 - 5749. [Abstract] [Full Text] [PDF]

				S. D. Sullivan and S. M. Moenter GABAergic Integration of Progesterone and Androgen Feedback to Gonadotropin-Releasing Hormone Neurons Biol Reprod, January 1, 2005; 72(1): 33 - 41. [Abstract] [Full Text] [PDF]

				G. N. Wade and J. E. Jones Neuroendocrinology of nutritional infertility Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2004; 287(6): R1277 - R1296. [Abstract] [Full Text] [PDF]

				S. D. Sullivan and S. M. Moenter Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: Implications for a common fertility disorder PNAS, May 4, 2004; 101(18): 7129 - 7134. [Abstract] [Full Text] [PDF]

				S. D. Sullivan and S. M. Moenter {gamma}-Aminobutyric Acid Neurons Integrate and Rapidly Transmit Permissive and Inhibitory Metabolic Cues to Gonadotropin-Releasing Hormone Neurons Endocrinology, March 1, 2004; 145(3): 1194 - 1202. [Abstract] [Full Text] [PDF]

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