Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility and is associated with a hyperactive reproductive axis that may be driven by enhanced GABA activity in the brain (1). Research in a prenatally androgenised (PNA) mouse model of PCOS has identified increased arcuate nucleus (ARN) GABA neuron innervation of gonadotropin-releasing hormone (GnRH) neurons (2). While chronic activation of ARN GABA neurons in healthy mice can drive a PCOS-like phenotype, it is unclear whether inhibition of this population can ameliorate PCOS pathology.
To investigate the impact of chronic inhibition of ARN GABA neuron activity on reproductive function in the PNA mouse model of PCOS, a Cre-dependent viral vector for the inhibitory hM4Di DREADD (designer receptor exclusively activated by designer drugs) or an mCherry control was targeted to ARN GABA neurons in adult PNA (PCOS-like) and healthy vehicle control (VEH) vesicular GABA transporter (VGAT)-ires-Cre mice (n=6-7/group). On average, hM4Di was expressed in 41.5±7.9% of the ARN GABA neuron population, and activation of hM4Di by the designer drug clozapine N-oxide (CNO) caused a robust inhibition of the spontaneous firing activity of ARN GABA neurons in vitro (p=0.0001; n=11 cells, N=4 mice).
In vivo, CNO (5mg/kg) was chronically delivered via drinking water for three weeks. No effects of CNO were observed in PNA or VEH mCherry-expressing mice. In both PNA and VEH hM4Di-expressing mice, CNO delivery resulted in a rapid, long-lasting increase in bodyweight (p<0.0001) compared to baseline, but did not affect the typical acyclic phenotype observed in hM4Di-expressing PNA mice at baseline, nor impact circulating testosterone levels, pulsatile luteinising hormone secretion, ovarian morphology or GABA-to-GnRH neuron wiring.
These findings suggest that reducing the activity of ARN GABA neurons does not ameliorate pathology in a preclinical model of PCOS.