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-Aminobutyric Acid Neurons Integrate and Rapidly Transmit Permissive and Inhibitory Metabolic Cues to Gonadotropin-Releasing Hormone Neurons

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

Address all correspondence and requests for reprints to: Dr. Shannon M. Moenter, Department of Internal Medicine and Cell Biology, University of Virginia, P.O. Box 800578, Jefferson Park Avenue, Charlottesville, Virginia 22908. E-mail: smm4n{at}virginia.edu.

Negative energy balance inhibits fertility by decreasing GnRH release; however, the mechanisms are not well understood. GnRH neurons can be excited by activation of -aminobutyric acid (GABA)_A receptors, and GABAergic neurons provide a major synaptic input. We hypothesized that permissive metabolic signals mediated by leptin and inhibitory signals conveyed by neuropeptide Y (NPY) and opiates rapidly alter GABA_A receptor-mediated drive to GnRH neurons. In fed and fasted female mice, GABAergic postsynaptic currents (PSCs) were recorded from GnRH neurons before and after in vitro treatment with leptin, NPY, or met-enkephalin. Leptin increased PSC frequency in fed and fasted mice, indicating that it increased presynaptic activity. Leptin also increased PSC size. Inhibiting leptin receptor signaling pathways within GnRH neurons abolished the latter effect, indicating a direct action on these cells. In fed, but not fasted, mice, NPY and met-enkephalin decreased PSC frequency in an antagonist-reversible manner, but did not alter PSC size. NPY-1 receptor antagonists alone increased frequency in fed and fasted mice, as did opiate receptor blockade in fasted animals, suggesting that endogenous NPY and opiates modulate GABAergic drive to GnRH neurons. These data suggest that GABAergic afferents integrate metabolic signals for delivery to GnRH neurons. Decreased sensitivity to NPY and opiates in fasted mice indicate that these peptides send physiologically relevant signals regarding energy balance to GnRH neurons.

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