Direct Regulation of GnRH Neuron Excitability by Arcuate Nucleus POMC and NPY Neuron Neuropeptides in Female Mice

Hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons act to sense and coordinate the brain's responses to metabolic cues. One neuronal network that is very sensitive to metabolic status is that controlling fertility. In this study, we investigated the impact of neuropeptides released by NPY and POMC neurons on the cellular excitability of GnRH neurons, the final output cells of the brain controlling fertility. The majority (similar to 70%) of GnRH neurons were activated by alpha-melanocyte-stimulating hormone, and this resulted from the direct postsynaptic activation of melanocortin receptor 3andmelanocortin receptor 4. A small population ofGnRHneurons (similar to 15%) was excited by cocaine and amphetamine-regulated transcript or inhibited by beta-endorphin. Agouti-related peptide, released by NPY neurons, was found to have variable inhibitory (similar to 10%) and stimulatory (similar to 25%) effects upon subpopulations of GnRH neurons. A variety of NPY and pancreatic polypeptide analogs was used to examine potential NPY interactions with GnRH neurons. Although porcine NPY (Y1/Y2/Y5 agonist) directly inhibited the firing of approximately 45% of GnRH neurons, [Leu(31), Pro(34)]-NPY (Y1/Y4/Y5 agonist) could excite (56%) or inhibit (19%). Experiments with further agonists indicated that Y1 receptors were responsible for suppressing GnRH neuron activity, whereas postsynaptic Y4 receptors were stimulatory. These results show that the activity of GnRH neurons is regulated in a complex manner by neuropeptides released by POMC and NPY neurons. This provides a direct route through which different metabolic cues can regulate fertility. (Endocrinology 153: 5587-5599, 2012)