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. [Display omitted] •Male mice exhibit greater microglial depletion than females after PLX3397 treatment.•Female and male microglia upregulate different signaling pathways during depletion.•Transgenic mouse models show sex-dependent differences in microglial depletion efficacy. Le et al. examined the sex-dependent effects of a drug that removes microglia, called PLX3397. They revealed that male microglia are more susceptible to being depleted by PLX3397 than female microglia, and that this difference likely arises from distinct survival strategies employed by male and female microglia.