Timed microglia depletion promotes functional network reorganization and motor recovery after stroke

Pharmacological options to promote long-term rehabilitation after stroke remain limited. We investigated how short-term microglia depletion during the subacute phase after ischemic stroke affects functional recovery and neuronal network dynamics. Using a C57BL/6 wild-type stroke model, fine motor performance was assessed with a skilled reaching task while bilateral cortical activity was recorded longitudinally through epidural electrocorticography. Microglia were depleted between days 3 and 7 post-stroke using PLX5622, a colony-stimulating factor 1 receptor inhibitor. Microglia depletion resulted in near-complete restoration of fine motor function by day 7 and 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. Following repopulation, microglial cells showed altered morphology and gene expression profiles. These findings reveal that transient microglial modulation during the subacute phase after stroke promotes cortical network reorganization and motor recovery.