Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.
Nat Neurosci
; 22(3): 374-385, 2019 03.
Article
en En
| MEDLINE
| ID: mdl-30718903
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Esquizofrenia
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Sinapsis
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Microglía
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Plasticidad Neuronal
Tipo de estudio:
Etiology_studies
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Prognostic_studies
Límite:
Adolescent
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Adult
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Aged
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Nat Neurosci
Asunto de la revista:
NEUROLOGIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos