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Original Investigation
March 18, 2020

Transcriptomic Landscape and Functional Characterization of Induced Pluripotent Stem Cell–Derived Cerebral Organoids in Schizophrenia

Author Affiliations
  • 1Center for Genomic Medicine, Massachusetts General Hospital, Boston
  • 2Chemical Biology Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge
  • 3Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
  • 4Schizophrenia and Bipolar Disorder Program, McLean Hospital, Belmont, Massachusetts
  • 5Program in Neuroscience, Harvard University, Cambridge, Massachusetts
  • 6Program in Chemical Biology, Harvard University, Cambridge, Massachusetts
  • 7Harvard Stem Cell Institute, Cambridge, Massachusetts
JAMA Psychiatry. Published online March 18, 2020. doi:10.1001/jamapsychiatry.2020.0196
Key Points

Question  What cellular processes are dysregulated in cerebral organoids generated from stem cells with patient-specific genetic backgrounds in schizophrenia?

Findings  In this case-control study, cerebral organoids from patients with schizophrenia showed differences in the pattern of expression of genes involved in synaptic biology, neurodevelopment, and immune response as well as genes involved in mitochondrial function and modulation of excitation/inhibition balance. Cerebral organoids showed specific deficits in mitochondrial physiology and a diminished response to stimulation and depolarization.

Meaning  Patient-specific 3-dimensional brain organoids may reveal differences in specific biological pathways in schizophrenia.

Abstract

Importance  Three-dimensional cerebral organoids generated from patient-derived induced pluripotent stem cells (iPSCs) may be used to interrogate cellular-molecular underpinnings of schizophrenia.

Objective  To determine transcriptomic profiles and functional characteristics of cerebral organoids from patients with schizophrenia using gene expression studies, complemented with investigations of mitochondrial function through measurement of real-time oxygen consumption rate, and functional studies of neuronal firing with microelectrode arrays.

Design, Setting, and Participants  This case-control study was conducted at Massachusetts General Hospital between 2017 and 2019. Transcriptomic profiling of iPSC-derived cerebral organoids from 8 patients with schizophrenia and 8 healthy control individuals was undertaken to identify cellular pathways that are aberrant in schizophrenia. Induced pluripotent stem cells and cerebral organoids were generated from patients who had been diagnosed as having schizophrenia and from heathy control individuals.

Main Outcomes and Measures  Transcriptomic analysis of iPSC-derived cerebral organoids from patients with schizophrenia show differences in expression of genes involved in synaptic biology and neurodevelopment and are enriched for genes implicated in schizophrenia genome-wide association studies (GWAS).

Results  The study included iPSC lines generated from 11 male and 5 female white participants, with a mean age of 38.8 years. RNA sequencing data from iPSC-derived cerebral organoids in schizophrenia showed differential expression of genes involved in synapses, in nervous system development, and in antigen processing. The differentially expressed genes were enriched for genes implicated in schizophrenia, with 23% of GWAS genes showing differential expression in schizophrenia and control organoids: 10 GWAS genes were upregulated in schizophrenia organoids while 15 GWAS genes were downregulated. Analysis of the gene expression profiles suggested dysregulation of genes involved in mitochondrial function and those involved in modulation of excitatory and inhibitory pathways. Studies of mitochondrial respiration showed lower basal consumption rate, adenosine triphosphate production, proton leak, and nonmitochondrial oxygen consumption in schizophrenia cerebral organoids, without any differences in the extracellular acidification rate. Microelectrode array studies of cerebral organoids showed no differences in baseline electrical activity in schizophrenia but revealed a diminished response to stimulation and depolarization.

Conclusions and Relevance  Investigations of patient-derived cerebral organoids in schizophrenia revealed gene expression patterns suggesting dysregulation of a number of pathways in schizophrenia, delineated differences in mitochondrial function, and showed deficits in response to stimulation and depolarization in schizophrenia.

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