Investigating the NPY/AgRP/GABA to GnRH Neuron Circuit in Prenatally Androgenized PCOS-Like Mice

Polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility, is associated with altered signaling within the hormone-sensitive neuronal network that regulates gonadotropin-releasing hormone (GnRH) neurons, leading to a pathological increase in GnRH secretion. Circuit remodeling is evident between GABAergic neurons in the arcuate nucleus (ARN) and GnRH neurons in a murine model of PCOS. One-third of ARN GABA neurons co-express neuropeptide Y (NPY), which has a known yet complex role in regulating GnRH neurons and reproductive function. Here, we investigated whether the NPY-expressing subpopulation (NPY(ARN)) of ARN GABA neurons (GABA(ARN)) is also affected in prenatally androgenized (PNA) PCOS-like NPY(ARN) reporter mice [Agouti-related protein (AgRP)-Cre;τGFP]. PCOS-like mice and controls were generated by exposure to di-hydrotestosterone or vehicle (VEH) in late gestation. τGFP-expressing NPY(ARN) neuron fiber appositions with GnRH neurons and gonadal steroid hormone receptor expression in τGFP-expressing NPY(ARN) neurons were assessed using confocal microscopy. Although GnRH neurons received abundant close contacts from τGFP-expressing NPY(ARN) neuron fibers, the number and density of putative inputs was not affected by prenatal androgen excess. NPY(ARN) neurons did not co-express progesterone receptor or estrogen receptor α in either PNA or VEH mice. However, the proportion of NPY(ARN) neurons co-expressing the androgen receptor was significantly elevated in PNA mice. Therefore, NPY(ARN) neurons are not remodeled by prenatal androgen excess like the wider GABA(ARN) population, indicating GABA-to-GnRH neuron circuit remodeling occurs in a presently unidentified non-NPY/AgRP population of GABA(ARN) neurons. NPY(ARN) neurons do, however, show independent changes in the form of elevated androgen sensitivity.