Stroke remains a leading cause of long-term disability, with effective therapies hampered by an incomplete understanding of brain recovery mechanisms. Emerging evidence indicates that the interactions between the brain extracellular matrix (ECM) and glial cells1 critically contribute to post-stroke neuroplasticity and can help promote stroke recovery.We investigated the role of perineuronal nets (PNNs), facet-like ECM layers surrounding fast-spiking interneurons, in neurological recovery following focal cerebral ischemia in mice. Using superresolution stimulated emission depletion (STED), structured illumination (SR-SIM) microscopy, confocal microscopy, and advanced image analysis methods4,5, we examined PNN reorganization, synapse remodeling, and the involvement of microglia in these processes.Microglia-mediated post-stroke PNN remodeling. (A) 3D-STED microscopy of a single WFA-labelled PNN; (B) Microglia (Iba1, red) interacts with cortical interneurons (Kv3.1, green) and engulfs PNN matrix (white). (C) PNN facet size and (D) motor recovery after stroke.Transient alterations in PNNs facilitated dynamic reorganization of inhibitory input to motor cortical interneurons, preceding motor coordination recovery after stroke. Morphological changes in PNNs were microglia-mediated, as evidenced by increased phagocytosis of PNN components by microglia. Using co-cultures of primary neurons and microglia, we found that microglial motility, phagocytosis, and synapse remodeling are modulated by hyaluronic acid, a key PNN component.These findings indicate a novel mechanism of post-stroke neuroplasticity, which can be promoted by targeting the tripartite interaction between PNNs, synapses, and microglia.1Dzyubenko & Hermann. Semin Immunopathol 45, 377-387, doi:10.1007/s00281-023-00989-1 (2023).2Dzyubenko et al. Journal of Biomedical Science 30, 76, doi:10.1186/s12929-023-00971-x (2023).3Dzyubenko et al. Matrix Biol 74, 121-132, doi:10.1016/j.matbio.2018.08.001 (2018)