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Submitted on October 14, 2003
Accepted on November 21, 2003
1 Internal Medicine and Cell Biology, PO Box 800578, Jefferson Park Avenue, University of Virginia, Charlottesville, VA, 22908.
* To whom correspondence should be addressed. E-mail: smm4n{at}virginia.edu.
Negative energy balance inhibits fertility by decreasing GnRH release, however the mechanisms are not well understood. GnRH neurons are excited by activation of GABAA receptors (GABAAR), and GABAergic neurons provide a major synaptic input. We hypothesized permissive metabolic signals mediated by leptin and inhibitory signals conveyed by NPY and opiates rapidly alter GABAAR-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 it increased presynaptic activity. Leptin also increased PSC size. Inhibiting leptin receptor signaling pathways within GnRH neurons abolished the latter effect, indicating 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 endogenous NPY and opiates modulate GABAergic drive to GnRH neurons. These data suggest GABAergic afferents integrate metabolic signals for delivery to GnRH neurons. Decreased sensitivity to NPY and opiates in fasted mice indicate these peptides send physiologically relevant signals regarding energy balance to GnRH neurons.
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