Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids

Tomoyo Sawada, Thomas E. Chater, Yohei Sasagawa, Mika Yoshimura, Noriko Fujimori-Tonou, Kaori Tanaka, Kynon J.M. Benjamin, Apuã C.M. Paquola, Jennifer A. Erwin, Yukiko Goda, Itoshi Nikaido, Tadafumi Kato

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2695-2711
Number of pages17
JournalMolecular psychiatry
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Fingerprint

Dive into the research topics of 'Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids'. Together they form a unique fingerprint.

Cite this