1. Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia
- Author
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Marja Koskuvi, Šárka Lehtonen, Kalevi Trontti, Meike Keuters, Ying‐Chieh Wu, Hennariikka Koivisto, Anastasia Ludwig, Lidiia Plotnikova, Pekka L. J. Virtanen, Noora Räsänen, Satu Kaipainen, Ida Hyötyläinen, Hiramani Dhungana, Raisa Giniatullina, Ilkka Ojansuu, Olli Vaurio, Tyrone D. Cannon, Jouko Lönnqvist, Sebastian Therman, Jaana Suvisaari, Jaakko Kaprio, Markku Lähteenvuo, Jussi Tohka, Rashid Giniatullin, Claudio Rivera, Iiris Hovatta, Heikki Tanila, Jari Tiihonen, Jari Koistinaho, Neuroscience Center, SLEEPWELL Research Program, Department of Psychology and Logopedics, Faculty Common Matters (Faculty of Biology and Environmental Sciences), HUS Psychiatry, Clinicum, Department of Psychiatry, Institute for Molecular Medicine Finland, Helsinki In Vivo Animal Imaging Platform (HAIP), Claudio Rivera Baeza / Principal Investigator, Biosciences, Mind and Matter, Iiris Hovatta / Principal Investigator, and Genetics
- Subjects
GENES ,515 Psychology ,extracellular matrix ,Induced Pluripotent Stem Cells ,1184 Genetics, developmental biology, physiology ,RNA sequencing ,3124 Neurology and psychiatry ,Cellular and Molecular Neuroscience ,calcium imaging ,GLUTAMATE ,Mice ,monozygotic twins ,DIFFERENTIATION ,Prosencephalon ,Neurology ,Astrocytes ,Schizophrenia ,Animals ,Humans ,Genetic Predisposition to Disease ,cell transplantation - Abstract
Previous studies have implicated several brain cell types in schizophrenia (SCZ), but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases, such as SCZ. Human induced pluripotent stem cell (hiPSC)-derived astrocytes differentiated from five monozygotic twin pairs discordant for SCZ and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics, neuron-astrocyte co-cultures, and in humanized mice. We found gene expression and signaling pathway alterations related to synaptic dysfunction, inflammation, and extracellular matrix components in SCZ astrocytes, and demyelination in SCZ astrocyte transplanted mice. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Differentially expressed transcriptomes and signaling pathways related to synaptic functions, inflammation, and especially collagen and glycoprotein 6 pathways indicate abnormal extracellular matrix composition in the brain as one of the key characteristics in the etiology of SCZ.
- Published
- 2021