Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR-/-) and mice overexpressing C3a in the brain, we uncovered 2 opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR-/- mice; C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity, and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within a convenient time window holds translational promise to improve outcome after ischemic stroke.

Cognitive Neuroscience Institute of Neuroscience and Medicine Research Center Juelich Juelich Germany

Department of Informatics and Chemistry Faculty of Chemical Technology University of Chemistry and Technology Prague Czech Republic

Department of Laboratory Medicine Institute of Biomedicine Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Department of Neurology Faculty of Medicine University of Cologne and University Hospital Cologne Cologne Germany

Laboratory of Astrocyte Biology and CNS Regeneration Center for Brain Repair Department of Clinical Neuroscience Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Laboratory of Gene Expression Institute of Biotechnology Czech Academy of Sciences Prague Czech Republic

Laboratory of Regenerative Neuroimmunology Center for Brain Repair Department of Clinical Neuroscience Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Multimodal Imaging Group Max Planck Institute for Metabolism Research Cologne Germany

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The role of complement in kidney disease