Estrous cycle- and sex-dependent changes in pre- and postsynaptic GABAB control of GnRH neuron excitability

The GnRH neurons are the key neurons controlling fertility in mammals. Although γ-aminobutyric acid (GABA) plays an important role in the regulation of GnRH neurons, the role of GABA(B) receptors is poorly understood. Using GnRH-green fluorescent protein transgenic mice and a parahorizontal brain slice preparation, we have undertaken a series of electrophysiological experiments to examine 1) postsynaptic GABA(B) receptors expressed by GnRH neurons, and 2) presynaptic GABA(B) receptors located on the terminals of an important neural input to GnRH neurons originating from the anteroventral periventricular nucleus (AVPV). The GABA(B) receptor agonist baclofen induced a direct postsynaptic hyperpolarization of GnRH neurons through induction of an outward current blocked by barium. Baclofen also acted presynaptically to suppress AVPV-activated GABA- and glutamate-evoked postsynaptic currents in GnRH neurons. The number of GnRH neurons exhibiting postsynaptic GABA(B) receptors was significantly (P < 0.05) different in males (22%) and females (70%), whereas presynaptic GABA(B) modulation of AVPV afferents was the same in the two sexes. Across the estrous cycle, a striking approximately 70% reduction (P < 0.05) in presynaptic GABA(B) modulation of AVPV afferents to GnRH neurons was found on proestrus compared with diestrus and estrus. In contrast, postsynaptic GABA(B) receptors did not change. Together, these findings show that GABA(B) receptors are active at both pre- and postsynaptic sites to modulate the excitability of GnRH neurons. The balance of this pre- and postsynaptic activity is different between the sexes and changes in a dynamic manner across the estrous cycle.