Abstract: A method of replacing endogenous microglia of a subject’s brain, e.g., an adult subject, with transplanted donor microglia includes depleting at least a portion of the endogenous microglia by administering to the subject a Colony Stimulating Factor 1 Receptor (CSFR1) inhibitor, wherein the CSFR1 inhibitor is blood-brain barrier permeable and pharmacologically ablates endogenous microglia; optionally stopping administration of the CSFR1 inhibitor for a time sufficient to prevent ablation of the transplanted donor microglia; and transplanting the donor microglia into the brain of the subject to provide the transplanted donor microglia.