Significant Sex Differences in the Efficacy of the CSF1R Inhibitor-PLX5622 on Rat Brain Microglia Elimination

Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, and neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. Survival of the microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor (CSF1R). The inhibition of CSF1R by brain-permeant PLX5622 in the chow eliminates, within 5-10 days, ~90% of the microglia in female and male mice, thereby enabling the investigation of the roles of the microglia in health and pathological mice models. Because of a prevailing "impression" that PLX5622 is ineffective in rats, it has hardly been used in studies of adult rats. Here, we report that effective microglia elimination by PLX5622-chow in rats is highly sex-dependent. Our observations provide missing information for the limited use and interpretation of PLX5622 in biomedical studies of the microglia in rat models. The sex differences that are too often overlooked must be carefully considered and clearly emphasized.