Microglia: sculptors of the polycystic ovary syndrome (PCOS)-like brain?

In brief: Neuroendocrine dysfunction and transgenerational susceptibility associated with polycystic ovary syndrome (PCOS) suggest that programmed changes within the brain contribute to adult development of the syndrome. This review discusses a potentially important role for microglia in mediating prenatal androgen-programmed changes in the female brain that contribute to PCOS-like features. Abstract: Several lines of evidence support a role for the brain in both the development and maintenance of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility worldwide. Persistently elevated luteinizing hormone secretion and impaired gonadal steroid hormone feedback in PCOS patients suggest impairments within the neuronal networks that regulate the reproductive axis. Evidence from preclinical models has linked androgen excess during prenatal life with altered structure and function of the developing female brain that might underpin syndrome development in adulthood. Studies investigating the mechanisms by which excess androgens program changes in the female brain have highlighted an important role for microglia. This review discusses how these non-neuronal cells shape the developing female brain in response to excess androgens and focuses on how microglia may be involved in the development of the neuroendocrine dysfunctions associated with PCOS.

Morphological evidence indicates a role for microglia in shaping the PCOS-like brain.

Although polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility worldwide, the aetiology of the disorder remains poorly defined. Animal-based evidence highlights the brain as a prime suspect in both the development and maintenance of PCOS. Prenatally androgenised (PNA) models of PCOS exhibit excessive GABAergic wiring associated with PCOS-like reproductive deficits in adulthood, with aberrant brain wiring detected as early as postnatal day (P) 25, prior to disease onset, in the PNA mouse. The mechanisms underlying this aberrant brain wiring remain unknown. Microglia, the immune cells of the brain, are regulators of neuronal wiring across development, mediating both the formation and removal of neuronal inputs. Here, we tested the hypothesis that microglia play a role in the excessive GABAergic wiring that leads to PCOS-like features in the PNA brain. Using specific immunolabelling, microglia number and morphology associated with activation states were analysed in PNA and vehicle-treated controls across developmental timepoints, including embryonic day 17.5, P0, P25 and P60 (n = 7-14 per group), and in two regions of the hypothalamus implicated in fertility regulation. At P0, fewer amoeboid microglia were observed in the rostral preoptic area (rPOA) of PNA mice. However, the greatest changes were observed at P25, with PNA mice exhibiting fewer total microglia, and specifically fewer "sculpting" microglia, in the rPOA. Based on these findings, we assessed microglia-mediated refinement of GABAergic synaptic terminals at two developmental stages of peak synaptic refinement: P7 and P15 (n = 7 per group). PNA mice showed a reduction in the uptake of GABAergic synaptic material at P15. These findings reveal time-specific changes in the microglia population and refinement of GABAergic inputs in a mouse model of PCOS driven by prenatal androgen excess and suggest a role for microglia in shaping the atypical brain wiring associated with the development of PCOS features.