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-Aminobutyric Acid Receptors Excites Gonadotropin-Releasing Hormone Neurons
Departments of Internal Medicine (R.A.D., S.M.M.) and Cell Biology (S.M.M.) and National Science Foundation Center for Biological Timing (S.M.M.), University of Virginia, Charlottesville, Virginia 22908; and Division of Neuroscience (S.H., S.R.O.), Oregon National Primate Research Center, Beaverton, Oregon 97006
Address all correspondence and requests for reprints to: Suzanne M. Moenter, Ph.D., Associate Professor, Departments of Medicine and Cell Biology, University of Virginia, Jefferson Park Avenue, PO Box 800578, Room 7145 Multistory Building, Charlottesville, Virginia 22908-0578. E-mail: smm4n{at}virginia.edu.
-Aminobutyric acid (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 green fluorescent protein-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. Furthermore, 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.
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