Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids.
Tomoyo SawadaThomas E ChaterYohei SasagawaMika YoshimuraNoriko Fujimori-TonouKaori TanakaKynon J M BenjaminApuã C M PaquolaJennifer A ErwinYukiko GodaItoshi NikaidoTadafumi KatoPublished in: Molecular psychiatry (2020)
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.
Keyphrases
- induced pluripotent stem cells
- single cell
- bipolar disorder
- rna seq
- end stage renal disease
- cell proliferation
- ejection fraction
- genome wide
- newly diagnosed
- chronic kidney disease
- peritoneal dialysis
- major depressive disorder
- prognostic factors
- high throughput
- patient reported outcomes
- machine learning
- cerebral ischemia
- copy number
- deep learning
- dna methylation
- case report
- brain injury
- quantum dots
- patient reported
- blood brain barrier
- functional connectivity
- data analysis