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

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

doi:10.1038/s41380-020-0844-z

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.

Highlights

With cerebral organoids and forebrain neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) of monozygotic twins discordant for psychoses, we propose the disease-associated staged dysregulation of neuronal development in which deficits in Wnt signaling pathway precede the reduced proliferation and marked dorsal-ventral fate shift to neuronal network excitation and inhibition (E/I) balance tilted toward GABAergic interneuron differentiation
Previous studies have reported the alterations in neuronal fate specification toward increased ventralization/ GABAergic differentiation in iPSC-derived neuronal cells from the patients with bipolar disorder (BD) [44, 45]
They showed that LiCl can promote dorsalization of the patients’ neurons. This finding was confirmed by Kim et al [45] in which patient-derived neurons exhibited higher expression of GAD1 and increased GABAergic specification compared with healthy individuals

Summary

Introduction

Schizophrenia (SZ) and bipolar disorder (BD) are among the most intractable disorders in brain health Both illnesses share complex genetic/environmental etiologies, molecular neuropathology, neurodevelopmental origin, and a subset set of symptoms including psychosis. Taking neurodevelopmental origins into account, brain organoids derived from induced pluripotent stem cells (iPSCs) of the patients are an optimal tool to identify the cell-type-specific pathophysiology of SZ and BD. Mounting research using patient-derived iPSCs has proposed several cellular pathways altered in these psychiatric disorders, including synaptic function and Wnt signaling [8]. Most of these studies differentiated the iPSCs into a predefined specific cell type. To detect disease-specific alterations minimizing inter-individual genetic variations, we analyzed the organoids of a pair of monozygotic twins discordant for psychoses and verified the findings in two additional monozygotic twins discordant for SZ

Participants

Results

Discussion

Compliance with ethical standards

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