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

Carl M Sellgren1,2,3, Jessica Gracias4,5,6, Bradley Watmuff4,5

  • 1Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. carl.sellgren@ki.se.

Nature Neuroscience
|February 6, 2019
PubMed

Insights

Schizophrenia may involve excessive synapse elimination, a process mediated by microglia. The antibiotic minocycline reduced this pruning in vitro and may lower schizophrenia risk, suggesting a potential therapeutic target.

Area of Science:

  • Neuroscience
  • Psychiatry
  • Immunology

Background:

  • Reduced synapse density in schizophrenia suggests increased synapse elimination.
  • Microglia play a role in synaptic pruning.

Purpose of the Study:

  • To investigate microglia-mediated synapse elimination in schizophrenia.
  • To explore the role of complement component 4 (C4) variants.
  • To assess the effect of minocycline on synapse elimination and schizophrenia risk.

Main Methods:

  • Reprogrammed in vitro model of microglia-mediated synapse engulfment.
  • Analysis of patient-derived neural cultures and isolated synaptosomes.
  • Examination of schizophrenia risk-associated C4 variants.
  • Retrospective cohort study using electronic health records.

Main Results:

  • Increased synapse elimination observed in patient-derived cultures.
  • Abnormalities in microglia-like cells and synaptic structures contribute to excessive pruning.
  • Schizophrenia risk variants in C4 locus correlate with increased neuronal complement deposition and synapse uptake, but do not fully explain it.
  • Minocycline reduced microglia-mediated synapse uptake in vitro.
  • Minocycline use associated with a modest decrease in incident schizophrenia risk.

Conclusions:

  • Excessive synaptic pruning is implicated in schizophrenia pathogenesis.
  • Microglia-mediated synapse elimination is a potential therapeutic target for schizophrenia.
  • Minocycline may offer a protective effect against schizophrenia onset.

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