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

Nature neuroscience (2019-02-06)
Carl M Sellgren, Jessica Gracias, Bradley Watmuff, Jonathan D Biag, Jessica M Thanos, Paul B Whittredge, Ting Fu, Kathleen Worringer, Hannah E Brown, Jennifer Wang, Ajamete Kaykas, Rakesh Karmacharya, Carleton P Goold, Steven D Sheridan, Roy H Perlis
ABSTRACT

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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