Microglia are not required for normal postnatal brain development and cognitive function in the rat

Abstract The development, maintenance and survival of microglia, the brain’s resident immune cells, requires signalling via the colony stimulating factor 1 receptor (CSF1R). In mice, the Fms intronic regulatory element (FIRE), a highly conserved super enhancer, is required for CSF1R expression in microglia and germ-line deletion of FIRE leads to microglial deficiency. We have generated Csf1rΔFIRE/ΔFIRE (Fireko) rats using CRISPR/Cas9. Fireko rats are born at expected Mendelian frequency, grow normally and survive to adulthood. Like Fireko mice, they lack microglia and subpopulations of resident macrophages in kidney and heart, but retain the other brain associated macrophages and resident populations in the liver, spleen and lungs. In contrast to mutant mice, macrophages in the peritoneum are unaffected and CSF1R expression is not completely abolished in the blood. Aside from the loss of microglia-specific transcripts, the Fireko has no effect on expression of genes associated with neurons, oligodendrocytes or astrocytes in adult rats but is associated with detectable calcification in the thalamus. Despite the absence of microglia, we detected no significant differences in ethologically relevant behaviours compared to littermates. The results suggest that microglia are not essential for normal cognitive development. Fireko rats provide an alternative to mice as a model for human microglial deficiency and the functions of microglia in development and homeostasis in the brain. Competing Interest Statement The authors have declared no competing interest.