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This version published online on September 26, 2002
Molecular Endocrinology, doi:10.1210/me.2002-0163
Molecular Endocrinology Vol. 0, No. 2002 200201631-
doi:10.1210/me.2002-0163
Copyright © 2002 by the Endocrine Society.
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Submitted on May 2, 2002
Accepted on September 9, 2002

ACTIVATION OF GABAA RECEPTORS EXCITES GnRH NEURONS

R. Anthony DeFazio1, Sabine Heger1, Sergio R. Ojeda1, and Suzanne M. Moenter1*

1 Departments of Internal Medicine and Cell Biology, and NSF Center for Biological Timing, University of Virginia, Charlottesville, VA 22908, Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006

* To whom correspondence should be addressed. E-mail: smm4n{at}virginia.edu.

GABA, acting through GABAA receptors (GABAAR), is hypothesized to suppress reproduction by inhibiting GnRH secretion, but GABA actions directly on GnRH neurons are not well established. In GFP-identified adult mouse GnRH neurons in brain slices, gramicidin-perforated-patch-clamp experiments revealed the reversal potential (EGABA) for current through GABAARs was depolarized relative to the resting potential and that rapid GABA application elicited action potentials in GnRH neurons but not controls. The consequence of GABAAR activation depends on intracellular chloride levels, which are maintained by homeostatic mechanisms. Membrane proteins that typically extrude chloride (KCC-2 cotransporter, ClC-2 channel) were absent from the GT1-7 immortalized GnRH cell line and GnRH neurons in situ or were not localized to the proper cell compartment for function. In contrast, GT1-7 cells and some GnRH neurons expressed the chloride accumulating cotransporter NKCC-1. Patch-clamp experiments showed that blockade of NKCC hyperpolarized EGABA by lowering intracellular chloride. Regardless of reproductive state, rapid GABA application excited GnRH neurons. In contrast, bath application of the GABAAR agonist muscimol transiently increased then suppressed firing; suppression persisted 4-15 min. Rapid activation of GABAAR thus excites GnRH neurons whereas prolonged activation reduces excitability, suggesting the physiological consequence of synaptic activation of GABAAR in GnRH neurons is excitation.
Key words: GnRH • GABA • GABAA receptor • chloride • gramicidin • patch clamp




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