The microglial response to inhibition of Colony-Stimulating-Factor-1 Receptor by PLX3397 differs by sex in adult mice

Microglia, the resident macrophage of the brain, are derived from the yolk sac and colonize the brain before the blood-brain barrier forms. Once established, they expand locally and require Colony-stimulating factor 1 receptor (CSF1R) signaling for their development and maintenance. CSF1R inhibitors have been used extensively to deplete microglia in the healthy and diseased brain. In this study, we demonstrated sex-dependent differences in the microglial response to the CSF1R inhibitor PLX3397. Male mice exhibited greater microglial depletion compared to females. Transcriptomic and flow cytometry analysis revealed sex-specific differences in the remaining microglia population, with female microglia upregulating autophagy and proteostasis pathways while male microglia increased mitobiogenesis. Furthermore, manipulating key microglial receptors by using different transgenic mouse lines resulted in changes in depletion efficacies that were also sex-dependent. These findings suggest sex-dependent microglial survival mechanisms, which might contribute to the well-documented sex differences in various neurological disorders. To investigate the underlying mechanisms that gave rise to the sex-dependent disparity in PLX-induced microglial depletion, microglia from young male and female mice treated with either PLX or control chow were isolated by Fluorescence activated cell sorting (FACS), their total RNA were sequenced and subsequently analyzed.