Journal
MOLECULAR PSYCHIATRY
Volume 25, Issue 11, Pages 2695-2711Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-020-0844-z
Keywords
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Funding
- JSPS [25891032, 15K19753, 17K160407]
- RIKEN BSI
- JST CREST [JPMJCR16G3]
- Projects for Technological Development, Research Center Network for Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED)
- Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation (GRIFIN) from AMED [17km0405208h0002]
- MEXT/JSPS [18H05435, 18H05428, 17H01573]
- Grants-in-Aid for Scientific Research [18H05428, 25891032, 18H05435, 15K19753, 17H01573] Funding Source: KAKEN
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Despite extensive genetic and neuroimaging studies, detailed cellular mechanisms underlying schizophrenia and bipolar disorder remain poorly understood. Recent progress in single-cell RNA sequencing (scRNA-seq) technologies enables identification of cell-type-specific pathophysiology. However, its application to psychiatric disorders is challenging because of methodological difficulties in analyzing human brains and the confounds due to a lifetime of illness. Brain organoids derived from induced pluripotent stem cells (iPSCs) of the patients are a powerful avenue to investigate the pathophysiological processes. Here, we generated iPSC-derived cerebral organoids from monozygotic twins discordant for psychosis. scRNA-seq analysis of the organoids revealed enhanced GABAergic specification and reduced cell proliferation following diminished Wnt signaling in the patient, which was confirmed in iPSC-derived forebrain neuronal cells. Two additional monozygotic twin pairs discordant for schizophrenia also confirmed the excess GABAergic specification of the patients' neural progenitor cells. With a well-controlled genetic background, our data suggest that unbalanced specification of excitatory and inhibitory neurons during cortical development underlies psychoses.
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