GABAergic Neurons Integrate and Transmit Inhibitory and Permissive Signals to GnRH Neurons

Pulsatile release of gonadotropin releasing hormone (GnRH) is absolutely required for fertility, however, central mechanisms regulating GnRH neuron output are not well understood. Metabolic signals reflecting nutritional state and feedback from steroid hormones alter GnRH release. These signals may communicate to GnRH neurons directly and/or transynaptically. Because GnRH neurons receive a major input from the neurotransmitter GABA acting at GABA A receptors (GABA A R), we asked if the GABAergic system communicates steroid and metabolic information to these cells. GABA A R activation is excitatory in GnRH neurons, thus we first hypothesized signals that decrease GnRH release alter the excitatory nature of the response to GABA. Contrary to this hypothesis, GABA A R activation elicited action currents, the currents underlying action potentials, in GnRH neurons from both fed and fasted mice, indicating potent inhibition of fertility by fasting did not alter the excitatory response to GABA. We next hypothesized steroid and metabolic signals alter excitatory GABAergic drive to GnRH neurons and/or the response to GABA. GABAergic postsynaptic currents (PSCs), which represent endogenous synaptic GABAergic input, were recorded from GnRH neurons; PSC frequency, a measure of presynaptic drive, and PSC size, indicative of the postsynaptic response to GABA, were compared. Fasting decreased PSC frequency and size, whereas in vivo leptin treatment during fasting, which rescues fertility, restored values to levels seen in fed mice. In vitro, NPY and opiates, which inhibit fertility, rapidly decreased PSC frequency, whereas leptin rapidly increased both frequency and size. Postsynaptic leptin effects were likely via activation of functional leptin receptors in GnRH neurons. In vivo androgens, given prenatally or in adulthood, increased PSC iii frequency and size, possibly due to increased connectivity between GABAergic and GnRH neurons; progesterone treatment in adulthood had the opposite effect. Neural steroid derivatives allosterically modulated the postsynaptic response to GABA A R activation. Together, these data demonstrate nutritional state and steroid feedback are communicated to GnRH neurons at least partly through the GABAergic system. For the GnRH neuron, these changes will alter the probability for action potential firing and ultimately, hormone release. Thus GABAergic modulation of GnRH neurons may have important implications for central fertility regulation and forms of hypothalamic infertility.

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