Efficacy and sex differences in the effects on rat brain microglia of the colony-stimulating factor 1 receptor inhibitor-PLX5622

Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. The discovery that the survival of microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor (CSF1R), along with the development of the effective brain permeant CSF1R inhibitors PLX5622, has boosted the investigation of the role of microglia in health, disease and in relations to sex-bias. The effectiveness of PLX5622 in examining the role of microglia has mainly been demonstrated in mice. Surprisingly, despite the critical importance of rat models in brain research, there are only 4 publications in which PLX5622 was used to investigate the roles of microglia in adult rats. This has been attributed to the "impression" that PLX5622 is "ineffective in rats". In view of the importance and interest in the role of microglia, the indispensability of rats for in vivo electrophysiological brain studies and behavioral research and the high efficacy of PLX5622-chow in eliminating microglia from adult mice brains, we examined the effects of PLX5622-chow on the elimination of the microglia in adult female and male rats. We found significant differences in microglia elimination by ad libitum PLX5622 feeding in male and female rats in different brain regions with significantly greater effectivity in female brains. Our pragmatic study provides practical information on the use and design of PLX5622 in gender-related and rat brain preclinical microglia research.