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

doi:10.1038/s41380-020-0844-z

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^*

^*Corresponding author for this work

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

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 language	English (US)
Pages (from-to)	2695-2711
Number of pages	17
Journal	Molecular Psychiatry
Volume	25
Issue number	11
DOIs	https://doi.org/10.1038/s41380-020-0844-z
State	Published - Nov 1 2020

Funding

Acknowledgements We thank the Support Unit for Bio-Material Analysis at RIKEN CBS, with special thanks to K. Ohtawa, F. Sakai, and K. Fukumoto. We also thank N. Kume, Y. Hisano, and M. Kurosawa (RIKEN CBS) for technical support; A. Matsushima and M. Ishii (RIKEN BDR) for assistance with the infrastructure for the data analysis; H. Danno (Knowledge Palette, Inc.) for the development of data analysis software for single-cell transcriptomes; I. Asaka and members of his lab (CiRA, Kyoto Univ.) for practical training on the generation and maintenance of human iPSCs; T. Hayashi (RIKEN BDR), M. Toyoshima, T. Yoshikawa (RIKEN CBS), and H. Okano (Keio Univ.) for discussion; Y. Kageyama (RIKEN CBS), S. Nanko (Teikyo University), and Y. Okazaki (Nagasaki University) for clinical assessment; and C. Yokoyama (RIKEN CBS) for manuscript editing. We thank all the participants of the study. This work was supported by the JSPS Grant-in-Aid for Young Scientists (Start-up) (25891032) and JSPS Grant-in-Aid for Young Scientists (B) (15K19753 and 17K160407) to TS; funds from RIKEN BSI to YG; JST CREST (JPMJCR16G3) and the Projects for Technological Development, Research Center Network for Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED) to IN; the Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation (GRIFIN) from AMED (17km0405208h0002) and MEXT/JSPS Grants-in-Aid for Scientific Research (KAKENHI) (18H05435, 18H05428, and 17H01573) to TK.

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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Sawada, T., Chater, T. E., Sasagawa, Y., Yoshimura, M., Fujimori-Tonou, N., Tanaka, K., Benjamin, K. J. M., Paquola, A. C. M., Erwin, J. A., Goda, Y., Nikaido, I., & Kato, T. (2020). Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids. Molecular Psychiatry, 25(11), 2695-2711. https://doi.org/10.1038/s41380-020-0844-z

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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{\textquoteright} 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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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 2020, 'Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids', Molecular Psychiatry, vol. 25, no. 11, pp. 2695-2711. https://doi.org/10.1038/s41380-020-0844-z

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AU - Benjamin, Kynon J.M.

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AU - Erwin, Jennifer A.

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AU - Nikaido, Itoshi

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

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