Short-term microglia depletion via CSF-1R inhibition promotes functional network reorganization and motor recovery after cortical ischemia

Abstract

BACKGROUNDPharmacological options to promote long-term rehabilitation after stroke remain limited. Microglia play a complex role in post-stroke pathology, contributing both to repair and secondary injury. How short-term depletion during the subacute phase affects functional recovery remains unknown. METHODSWild-type mice were trained in a skilled reaching task and underwent permanent distal medial cerebral artery occlusion or sham intervention. Mice received either a colony-stimulating factor 1 receptor inhibitor or vehicle treatment between days 3 and 7 post-stroke to deplete microglia. Fine motor performance was assessed behaviorally while bilateral cortical activity was recorded longitudinally through epidural electrocorticography. RESULTSMicroglia depletion did not affect infarct size but resulted in near-complete restoration of fine motor function by day 7, coinciding with maximal microglial depletion. Recovery of fine motor function was accompanied by significant functional connectivity changes in bilateral sensorimotor networks, including increased beta-band connectivity in the ipsilesional motor cortex, which correlated with contralateral fine motor improvement. After microglial repopulation, cells showed altered morphology and gene expression profiles. CONCLUSIONSTransient microglial modulation during the subacute phase after stroke promotes cortical network reorganization and motor recovery, highlighting a potential time window for future translational studies.