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Nat Neurosci. 2019 Mar;22(3):374-385. doi: 10.1038/s41593-018-0334-7. Epub 2019 Feb 4.

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

Author information

1
Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. carl.sellgren@ki.se.
2
Department of Psychiatry, Harvard Medical School, Boston, MA, USA. carl.sellgren@ki.se.
3
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. carl.sellgren@ki.se.
4
Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
5
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
6
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
7
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
8
Schizophrenia and Bipolar Disorder Program, McLean Hospital, Belmont, MA, USA.
9
Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. rperlis@mgh.harvard.edu.
10
Department of Psychiatry, Harvard Medical School, Boston, MA, USA. rperlis@mgh.harvard.edu.

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.

PMID:
30718903
PMCID:
PMC6410571
[Available on 2019-09-01]
DOI:
10.1038/s41593-018-0334-7

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