1. In this study of 3-dimensional cerebral organoids of schizophrenia patients and healthy controls, differences were found in mitochrondrial function, response to stimulation and depolarization, ATP production, and overall pathway and neuronal generation deficits.
Evidence Rating Level: 3 (Average)
Patient-derived induced pluripotent stem cells (iPSCs) come from somatic cells through
cellular reprogramming methods, allowing for the genesis of new cells and tissues. iPSCs further allow for the study of cells associated with disease-specific genetic
predispositions, particularly ex vivo models of psychiatric conditions. Most studies of this
type are two-dimensional, while the current study undertook a three-dimensional
approach to iPSC-derived brain organoids. Specifically, this case-control study at
Massachusetts General Hospital sought to determine functional characteristics and
transcriptomic profiles of these cerebral organoids in individuals with Schizophrenia
using genome-wide association study (GWAS) information. A total of 16 participants
were selected, half of whom were diagnosed with Schizophrenia and the remaining half
were healthy controls (M [SD] age = 38.8 [12.0] years, 31.3% female). Significant gene
ontology processes such as neurogenesis, nervous system development, and neuronal
generation were downregulated in Schizophrenia patients, while antigen processing,
extracellular matrix organization, and cellular response to chemical stimulus were
upregulated in this group. Gene expression appeared to be significantly dysregulated in
genes associated with mitochondrial functioning as well as both inhibitory and excitatory
pathways. Mitochondrial respiration analyses suggested lower adenosine triphosphate
production, proton leak, basal consumption rate, and non-mitochondrial oxygen
consumption in schizophrenia cerebral organoids. No differences were noted in
baseline electrical activity in schizophrenia organoids following microelectrode array studies, but there was a notable reduction in response to depolarization and stimulation. Overall, this study of schizophrenia-related cerebral organoids suggests significant
dysregulation of several pathways, mitochondrial functionality, and response to
depolarization and stimulation.
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