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Published Online: 2 November 2023

Recapitulation of Perturbed Striatal Gene Expression Dynamics of Donors’ Brains With Ventral Forebrain Organoids Derived From the Same Individuals With Schizophrenia

Tomoyo Sawada, Ph.D. [email protected], André R. Barbosa, Ph.D., Bruno Araujo, Ph.D., Alejandra E. McCord, B.A., Laura D’Ignazio, Ph.D., Kynon J.M. Benjamin, Ph.D., Bonna Sheehan, B.Sc., Michael Zabolocki, B.Sc., Arthur Feltrin, Ph.D., Ria Arora, B.Sc., Anna C. Brandtjen, B.A., Joel E. Kleinman, M.D., Ph.D., Thomas M. Hyde, M.D., Ph.D., Cedric Bardy, Ph.D., Daniel R. Weinberger, M.D., Apuã C.M. Paquola, Ph.D., and Jennifer A. Erwin, Ph.D. [email protected]Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 181, Number 6
https://doi.org/10.1176/appi.ajp.20220723
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Abstract

Objective:

Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs).

Methods:

VFOs were generated from postmortem dural fibroblast–derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs).

Results:

Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort.

Conclusions:

The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type–specific neurodevelopmental phenotypes in a dish.

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Supplementary Material

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 181 • Number 6 • June 01, 2024
Pages: 493 - 511
PubMed: 37915216

History

Received: 19 August 2022
Revision received: 22 May 2023
Accepted: 14 June 2023
Published online: 2 November 2023
Published in print: June 01, 2024

Keywords

  1. Genetics/Genomics
  2. Schizophrenia Spectrum and Other Psychotic Disorders

Authors

Affiliations

Tomoyo Sawada, Ph.D. [email protected]
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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André R. Barbosa, Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Bruno Araujo, Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Alejandra E. McCord, B.A.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Laura D’Ignazio, Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Kynon J.M. Benjamin, Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Bonna Sheehan, B.Sc.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Michael Zabolocki, B.Sc.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Arthur Feltrin, Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Ria Arora, B.Sc.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Anna C. Brandtjen, B.A.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Joel E. Kleinman, M.D., Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Thomas M. Hyde, M.D., Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Cedric Bardy, Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Daniel R. Weinberger, M.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Apuã C.M. Paquola, Ph.D.
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Jennifer A. Erwin, Ph.D. [email protected]
Lieber Institute for Brain Development, Baltimore (Sawada, Barbosa, Araujo, McCord, D’Ignazio, Benjamin, Sheehan, Feltrin, Arora, Brandtjen, Kleinman, Hyde, Weinberger, Paquola, Erwin); Department of Neurology (D’Ignazio, Benjamin, Kleinman, Hyde, Weinberger, Paquola, Erwin), Department of Psychiatry and Behavioral Sciences (Benjamin, Kleinman, Hyde, Weinberger), and Department of Neuroscience (Weinberger, Erwin), Johns Hopkins School of Medicine, Baltimore; South Australian Health and Medical Research Institute, Laboratory for Human Neurophysiology and Genetics, Adelaide (Zabolocki, Bardy); Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide (Zabolocki, Bardy).
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Notes

Send correspondence to Dr. Sawada ([email protected]) and Dr. Erwin ([email protected]).

Funding Information

Supported by the Lieber Institute for Brain Development, a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation, the MGH Collaborative Center for X-Linked Dystonia-Parkinsonism (Drs. Erwin and Paquola), the Maryland Stem Cell Research Fund (Dr. D’Ignazio), and NIH (Dr. Benjamin, grant T32MH015330).Dr. Kleinman has served as a consultant for Merck on an antipsychotic drug trial. Dr. Weinberger has served on the advisory boards of Sage Therapeutics and Pasithea Therapeutics. The other authors report no financial relationships with commercial interests.

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