The Role of Microglia in the Polycystic Ovary Syndrome (PCOS)-Like Brain

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, affecting roughly 1 in 8 women of reproductive age. Accumulating evidence from animal models suggests that the brain plays a key role in the development and maintenance of PCOS. In a well-characterised prenatally androgenised (PNA) mouse model of PCOS, aberrant neuronal wiring associated with PCOS deficits in adulthood are detected as early as postnatal day (P) 25, prior to disease onset. However, the mechanisms by which prenatal androgen exposure alters brain wiring remains unknown. Microglia, the immune cells of the brain, are active sculptors of neuronal wiring across development, mediating both the formation and removal of neuronal inputs. Therefore, microglia may play an important role in driving the abnormal neuronal wiring that leads to PCOS-like features in the PNA brain. Here, to assess whether microglia are altered in the brain of PNA mice, microglia number and morphology-associated activation states were quantified in two hypothalamic regions implicated in fertility regulation. Microglia were identified by immunolabelling for the microglia-specific marker, Iba-1, across developmental timepoints, including embryonic day 17.5, P0, P25, P40 and P60 (n = 7–14/group). At P0, PNA mice had significantly fewer “activated” amoeboid microglia compared to controls (P < 0.05). Later in development at P25, PNA mice exhibited significantly fewer “sculpting” microglia (P < 0.001), whereas at P60, PNA mice possessed a greater number of “activated” amoeboid microglia relative to controls (P < 0.01). This study demonstrates time-specific changes in the number and morphology of microglia in a mouse model of PCOS and suggests a role for microglia in driving the brain wiring abnormalities associated with PCOS. These findings support the need for future functional experiments to determine the relative importance of microglia function in shaping the PCOS-like brain and associated reproductive dysfunction.