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Endogenous -Aminobutyric Acid Can Excite Gonadotropin-Releasing Hormone Neurons

Department of Internal Medicine and Cell Biology, University of Virginia (S.M.M.), Charlottesville, Virginia 22908; and Department of Physiology and Biophysics, Miller School of Medicine, University of Miami (R.A.D.), Miami, Florida 33136

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

-Aminobutyric acid (GABA) provides a major synaptic input to GnRH neurons. GnRH neurons maintain high intracellular chloride levels and respond to exogenous GABA with depolarization and action potential firing. We examined the role of synaptic GABA type A receptor (GABA_AR) activation on the firing activity of GnRH neurons. Targeted extracellular recordings were used to detect firing activity of GnRH neurons in brain slices from adult female mice. Because the brain slice preparation preserves both glutamatergic and GABAergic neuronal networks, the effects of GABA_ARs on GnRH neurons were isolated by blocking ionotropic glutamatergic receptors (iGluR). With iGluR blocked, many GnRH neurons remained spontaneously active. Consistent with an excitatory role for GABA, subsequent blockade of GABA_ARs suppressed the firing rate in active cells from diestrous females by approximately 40% (P < 0.05; n = 10). GABA_AR blockade did not affect inactive cells (n = 7), indicating that GABA_AR-mediated inhibition was not responsible for the lack of firing. In prenatally androgenized females, GnRH neurons exhibit larger, more frequent GABAergic postsynaptic currents than control females. Most cells from prenatally androgenized animals fired spontaneously, and the firing rate was suppressed approximately 80% after GABA_AR blockade (P < 0.01; n = 8). Blocking GABA_AR without blocking iGluRs increased the firing rate in GnRH neurons from diestrous females (P < 0.05; n = 6), perhaps attributable to hyperexcitability within the slice network. Our results indicate that GABAergic inputs help generate a portion of action potentials in GnRH neurons; this fraction depends on the level of GABA transmission and postsynaptic responsiveness. The complexities of the GnRH neuron response to GABA make this a potentially critical integration point for central regulation of fertility.

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