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Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia.
- Source :
-
Nature neuroscience [Nat Neurosci] 2020 Nov; Vol. 23 (11), pp. 1352-1364. Date of Electronic Publication: 2020 Oct 23. - Publication Year :
- 2020
-
Abstract
- The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.
- Subjects :
- Adult
Coculture Techniques
Encephalitis metabolism
Gene Expression
Glutamic Acid metabolism
Humans
Induced Pluripotent Stem Cells physiology
Male
Middle Aged
Mitochondria metabolism
Young Adult
gamma-Aminobutyric Acid metabolism
Cerebral Cortex metabolism
Interneurons metabolism
Microglia metabolism
Schizophrenia metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1726
- Volume :
- 23
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Nature neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 33097921
- Full Text :
- https://doi.org/10.1038/s41593-020-00724-1