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Sellgren, Carl M; Gracias, Jessica; Watmuff, Bradley; Biag, Jonathan D; Thanos, Jessica M; Whittredge, Paul B; Fu, Ting; Worringer, Kathleen; Brown, Hannah E; Wang, Jennifer; Kaykas, Ajamete; Karmacharya, Rakesh; Goold, Carleton P; Sheridan, Steven D; Perlis, Roy H
Nature neuroscience, 03/2019, Letnik: 22, Številka: 3Journal Article
Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.
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