Investigating GABA neuron-specific androgen receptor knockout in two hyperandrogenic models of PCOS.

Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links developmental or chronic exposure to hyperandrogenism with programming and evoking the reproductive and metabolic traits of PCOS. While critical androgen targets remain to be determined, central GABAergic neurons are postulated to be involved. Here, we tested the hypothesis that androgen signalling in GABAergic neurons is critical in PCOS pathogenesis in two well-characterised hyperandrogenic mouse models of PCOS. Using cre-lox transgenics, GABA-specific androgen receptor knockout (GABARKO) mice were generated and exposed to either acute prenatal androgen excess (PNA) or chronic periperpubertal androgen excess (PPA). Females were phenotyped for reproductive and metabolic features associated with each model and brains of PNA mice were assessed for elevated GABAergic input to GnRH neurons. Reproductive and metabolic dysfunction induced by PPA, including acyclicity, absence of corpora lutea, obesity, adipocyte hypertrophy and impaired glucose homeostasis, was not different between GABARKO and WT mice. In PNA mice, acyclicity remained in GABARKO mice while ovarian morphology and luteinising hormone secretion was not significantly impacted by PNA or genotype. However, PNA predictably increased the density of putative GABAergic synapses to GnRH neurons in adult WT mice, and this PNA-induced plasticity was absent in GABARKO mice. Together, these findings suggest that while direct androgen signalling in GABA neurons is largely not required for the development of PCOS-like traits in androgenised models of PCOS, developmental programming of GnRH neuron innervation is dependent upon androgen signalling in GABA neurons.