Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia. Issue 4 (22nd December 2021)

• Record Type: Journal Article
• Authors: Koskuvi, Marja; Lehtonen, Šárka; Trontti, Kalevi; Keuters, Meike; Wu, Ying‐Chieh; Koivisto, Hennariikka; Ludwig, Anastasia; Plotnikova, Lidiia; Virtanen, Pekka L. J.; Räsänen, Noora; Kaipainen, Satu; Hyötyläinen, Ida; Dhungana, Hiramani; Giniatullina, Raisa; Ojansuu, Ilkka; Vaurio, Olli; Cannon, Tyrone D.; Lönnqvist, Jouko; Therman, Sebastian; Suvisaari, Jaana; Kaprio, Jaakko; Lähteenvuo, Markku; Tohka, Jussi; Giniatullin, Rashid; Rivera, Claudio; Hovatta, Iiris; Tanila, Heikki; Tiihonen, Jari; Koistinaho, Jari
• Is Part Of: Glia. Volume 70:Issue 4(2022)
• Page Start: 650
• Page End: 660
• Publication Date: 2021-12-22
• Subjects: calcium imaging -- cell transplantation -- extracellular matrix -- induced pluripotent stem cells -- monozygotic twins -- RNA sequencing; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.24131
• Languages: English
• ISSNs: 0894-1491

Abstract

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. Main Points: hiPSC astrocytes from patients with schizophrenia have abnormal transcriptome. Aberrant signaling pathways were related to synaptic functions, inflammation, and extracellular matrix. Astrocytes altered both cultured neuronal and brain functions.