Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

• Published in: Genome medicine Vol. 12; no. 1; p. 34
• Main Authors: Kathuria, Annie, Lopez-Lengowski, Kara, Vater, Magdalena, McPhie, Donna, Cohen, Bruce M, Karmacharya, Rakesh
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19.04.2020; BioMed Central; BMC
• Subjects: Adult; Analysis; Biology; Bipolar disorder; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; Brain research; Cell Adhesion; Cells, Cultured; Chondroitin Sulfate Proteoglycans - genetics; Chondroitin Sulfate Proteoglycans - metabolism; Depolarization; Endoplasmic reticulum; Ethanol; Experiments; Female; Fibroblasts; Gene expression; Genes; Genetic aspects; Genomes; Genomics; Humans; Immunoglobulins; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; iPSC; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Male; MAM; Medical research; Membrane Potentials; Mental disorders; Methods; Middle Aged; Mitochondria; NCAN; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neural Stem Cells - physiology; Neurocan; Neurons; Neurophysiology; Neurosciences; Neurotransmission; Organoid; Organoids; Organoids - cytology; Organoids - metabolism; Organoids - physiology; Patients; Penicillin; Pluripotency; Ribonucleic acid; RNA; Schizophrenia; Somatic cells; Stem cells; Transcriptome; Immune signaling; NCAN; Cell adhesion; iPSC; MAM; Bipolar disorder; Organoid; Endoplasmic reticulum
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-020-00733-6

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 disease-specific genetic backgrounds. 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. 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. 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.