Journal
NATURE NEUROSCIENCE
Volume 22, Issue 3, Pages 374-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-018-0334-7
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Funding
- National Institute of Mental Health [P50-MH106933]
- National Human Genome Research Institute [P50-MH106933]
- Swedish Research Council [2017-02559]
- Marianne and Marcus Wallenberg Foundation [MMW 2017.0118]
- National Institute of Mental Health Biobehavioral Research Award for Innovative New Scientists (BRAINS) [R01MH113858]
- Swedish Research Council [2017-02559] Funding Source: Swedish Research Council
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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.
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