Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Nat Neurosci. 2019 Mar;22(3):374-385. doi: 10.1038/s41593-018-0334-7. Epub 2019 Feb 4.
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.
突触密度在精神分裂症患者死后的皮质组织中降低，提示突触消除增加。使用体外重编程的小胶质细胞介导的突触吞噬模型，我们在患者来源的神经培养物和分离的突触体中证明了突触消除的增加。这种过度的突触修剪反映了小胶质样细胞和突触结构的异常。此外，我们发现人类补体成分 4 基因座内与精神分裂症风险相关的变异与神经元补体沉积和突触摄取的增加有关；然而，它们并不能完全解释观察到的突触摄取增加。最后，我们证明抗生素米诺环素可减少体外小胶质细胞介导的突触摄取，并且与电子健康记录中抽取的年轻成年人队列中的其他抗生素相比，其使用与精神分裂症发病风险的适度降低相关。这些发现表明过度修剪可能是延迟或预防高危人群精神分裂症发病的潜在目标。
