Abstract
Neuroinflammation Synapses appear to provide the initiation sites of neuronal damage in human multiple sclerosis (MS), but how this synapse loss occurs, how it affects circuit activity, and how it could be prevented are all unknown. Jafari et al. describe a mouse model of cortical MS pathology designed to address these questions. They used structural and functional in vivo imaging to reveal the pathogenesis, functional consequences, and therapeutic targeting of immune-mediated synapse loss in inflamed cortical gray matter. Low-dose myelin protein immunization and stereotactic injection of cytokines implicated in MS were used to target MS-like neuroinflammatory lesions to mouse cortex. Single-cell and ultrastructural analysis revealed the loss of one-third of all synapses across both cortical hemispheres. Synapse pathology was completely reversible within a few weeks, after cortical inflammation had subsided. Localized calcium accumulations primed individual synapses for pruning by invading macrophages and activated microglia. Furthermore, an anti–colony-stimulating factor 1 receptor antagonist inhibited synapse pruning and cortical synapse loss. Thus, synaptoprotective therapeutic approaches may be feasible in MS-like neuroinflammatory disease. Nat. Neurosci. 10.1038/s41593-020-00780-7 (2021).
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