No access
Article
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., … Show All … , 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
Track CitationsAdd to favorites
Get Access

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.

Get full access to this article

View all available purchase options and get full access to this article.

Get Access

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

Details

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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author
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).
View all articles by this author

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.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard
Tips for downloading citations

View Options

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Item saved, go to cart
Purchase Options

Purchase this article to access the full text.

PPV Articles - American Journal of Psychiatry

PPV Articles - American Journal of Psychiatry

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

View options

PDF/EPUB

View PDF/EPUB

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Share article link

Share

×

As described within the American Psychiatric Association (APA)'s Privacy Policy and Terms of Use, this website utilizes cookies, including for the purpose of offering an optimal online experience and services tailored to your preferences. Please read the entire Privacy Policy and Terms of Use. By closing this message, browsing this website, continuing the navigation, or otherwise continuing to use the APA's websites, you confirm that you understand and accept the terms of the Privacy Policy and Terms of Use, including the utilization of cookies.