Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

Abstract

Background: Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with diseasespecific genetic backgrounds. Methods: Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays.Results: RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER-mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids.Conclusions: Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.

The Relationship between the Level of Anterior Cingulate Cortex Metabolites, Brain-Periphery Redox Imbalance, and the Clinical State of Patients with Schizophrenia and Personality Disorders

“…According to our earlier hypothesis and limited data, the observed changes in glutamate levels can be associated with the mitochondrial metabolism of the brains of patients with schizophrenia. The role of mitochondrial function in the etiopathogenesis of schizophrenia has recently gained importance, as indicated by genetic, proteomic, enzymatic, and anatomical abnormalities [ 71 , 72 ]. An additional argument linking the appropriate patterns of brain metabolites with the changes in the brain’s bioenergy balance are the results indicating a reduction in the ability of pyramidal neurons to generate bioenergetic substrates from glucose via glycolytic pathways and the observed decrease in lactate production in schizophrenic patients.…”

“…Two-dimensional T2-weighted images in axial, coronal, and sagittal plane were performed to visualize anatomical brain structures and plan position of the VOI (rectangle) for spectroscopy [ 71 ]. Spectroscopy was performed using a single-voxel technique (SVS).…”

Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease

“…Compared to 2D cultures, COs reproduce human conditions like AD more closely [35,36,45,138]. Single cell transcriptomics of patient derived COs have shown considerable promise in identifying novel biomarker candidates [15,132,[171][172][173]. β and γ-secretase inhibitors decrease Aβ and pTau accumulation in COs [35,36,45,138].…”

“…There are also sex-specific trends in AD indicated by transcriptomic alterations in particular cell types [ 130 ], which may lend an important insight to the selection of iPSC donors for AD CO models. Novel disease-specific deficits in neuronal differentiation, neurodevelopment and neurotransmission have been identified via scRNA-Seq in CO models for bipolar disorder, schizophrenia and autism spectrum disorder (ASD) [ 131 – 133 ]. Although these studies may not be directly generalizable to neurodegenerative conditions, they exemplify an ideal strategy to detect disease-specific transcriptomic changes at the cellular level, which may be of great benefit to further our understanding of ND mechanisms.…”

The Role of Brain Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia

“…Human induced pluripotent stem cells (iPSC) provide us with the opportunity to develop physiologically relevant models of psychiatric disorders such as schizophrenia and bipolar disorder [28][29][30]. The use of iPSC-derived models to investigate schizophrenia pathophysiology has revealed disease-related changes in gene expression as well as deficits in specific neuronal subtypes [31,32].…”