Replacement of microglia by brain-engrafted macrophages provide protection against concussive injury

Brain resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during therapeutic whole-brain irradiation prevents synaptic loss and long-term recognition memory deficits. Here we demonstrate that after concurrent therapeutic whole-brain irradiation and microglia depletion, macrophages originating from circulating monocytes engraft into the brain and replace the microglia pool. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype which resembles both monocytes and embryonic microglia. In response to a secondary concussive brain injury, brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to that of microglia from normal brain. Notably, mice bearing engrafted macrophages are spared from concussive injury-induced memory loss. Taken together, our data demonstrate that replacement of microglia by brain-engrafted macrophages provides protection against concussive brain injury-induced memory deficits.