| RRC ID |
62331
|
| 著者 |
Sawada T, Chater TE, Sasagawa Y, Yoshimura M, Fujimori-Tonou N, Tanaka K, Benjamin KJM, Paquola ACM, Erwin JA, Goda Y, Nikaido I, Kato T.
|
| タイトル |
Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids.
|
| ジャーナル |
Mol Psychiatry
|
| Abstract |
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.
|
| 巻・号 |
25(11)
|
| ページ |
2695-2711
|
| 公開日 |
2020-11-1
|
| DOI |
10.1038/s41380-020-0844-z
|
| PII |
10.1038/s41380-020-0844-z
|
| PMID |
32764691
|
| PMC |
PMC7577852
|
| MeSH |
Cerebral Cortex* / cytology
Cerebral Cortex* / pathology
Humans
Induced Pluripotent Stem Cells / pathology
Male
Organoids* / cytology
Organoids* / pathology
Psychotic Disorders / genetics*
Psychotic Disorders / pathology*
Sequence Analysis, RNA
Single-Cell Analysis*
Twins, Monozygotic / genetics*
Twins, Monozygotic / psychology*
|
| IF |
12.384
|
| リソース情報 |
| ヒト・動物細胞 |
409B2(HPS0076)
NB1RGB(RCB0222) |
