191 White matter microglia heterogeneity observed with age145, may result from compromised function of microglia/macrophages146. Here, rejuvenation of microglia to restore remyelination capacity could provide a valuable tool to halt, or at the least, slow disease progression. Several microglial depletion and repopulation strategies have been developed in recent years: genetic, toxin-based and pharmacological147,148, with the latter having potential translational value. Experimentally eliminating the majority of microglia using orally administered inhibitors of the pro-survival receptor CSF1R has been shown to improve clinical or neuropathological outcomes in various models of CNS disease and dysfunction (reviewed in149), including in the white matter150,151. A clinical trial of the CSF1R inhibitor pexidartinib for the treatment of glioma demonstrated that the drug was well tolerated in humans, although post-mortem brain tissue analysis indicated variable impact on CNS IBA1+ cells152. In mice, removal of CSF1R inhibitor from the diet induces microglia repopulation and can in some contexts be associated with altered transcriptomes and improved outcome153-155, which may point to expansion of protective or regenerativemicroglia states. Clinical outcome would likely be influenced by timing and dosing of depletion in relation to the occurrence of pathology, whether microglial repopulation occurs, and whether repopulated microglia have altered function149. Interestingly, depletion/ repopulation of microglia in aged mice does appear to have a rejuvenating effect on their transcriptome, associated with improved cognition153. However, potential off-target effects of CSF1R inhibition on other CNSmacrophages or receptorsmay need to be taken into account156, in addition to avoiding microglia depletion in contexts where they are protective157-160. Altogether, these studies provide an encouraging prospect of therapeutically targeting microglia in the injured CNS. Future work is needed to determine the differential impact of drugs on specific microglia states, and whether this is influenced by CNS region and timing of treatment post-insult. Conclusions and future aspects Microglia have regionally defined functions in the CNS relating to development, homeostasis, ageing, and response to injury, reflecting the local needs of the CNS parenchyma. Indeed, microglia show regional differences in density, morphology, and transcriptome between white and grey matter. In addition, heterogeneity of white matter microglial responses has been observed in development, ageing, inflammatory white matter diseases, leukodystrophies and neurodegenerative diseases (Fig. 4). Furthermore, transcriptomic and proteomic approaches have identified microglial states in the white matter in development and ageing, and during de- and re-myelination. There are however key questions that need to be addressed to fully understand white matter microglial heterogeneity and its relevance to CNS health. Firstly, ‘how similar are mouse (or other animals) and human white matter microglia?’ Although recent studies have shown some similarities in mouse versus human transcriptomic states, differences have also been observed which may be important for CNS health, disease, or recovery. For example, DAM signatures found in mouse models do not completely overlap with signatures in human AD brains129, nor in MS lesions90,91. One must take into account confounding factors when comparing mouse to human microglia, such as species differences regarding expression of key genes regulating microglia, differences in age, environmental exposures (e.g. infection and vaccination status), genetic variability, and CNS regions assessed. Secondly, ‘what is the function of specific microglial states in the white matter?’ Recent work has implicated phagocytosis as an important function of white matter microglia in development and ageing,
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