Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning

By C. Sellgren, Jessica Gracias, Bradley Watmuff, J. Biag, Jessica M. Thanos, Paul B. Whittredge, Ting Fu, Kathleen A. Worringer, Hannah E. Brown, Jennifer Wang and 5 more. Nature Neuroscience, 2019

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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. Postmortem studies indicate reduced synaptic density in schizophrenia. Sellgren et al. show increased synaptic pruning in patient-derived cell models and provide evidence that C4 risk variants increase engulfment, while minocycline decreases it.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/42da7efd0a2a9fed5e6c23c79eb37f1980fd6a00