Patient iPSC-astrocytes show transcriptional and functional dysregulation in schizophrenia

Marja Koskuvi; Šárka Lehtonen; Kalevi Trontti; Meike Hedwig Keuters; Ying Chieh Wu; Hennariikka Koivisto; Anastasia Ludwig; L. M. Plotnikova; Pekka L. J. Virtanen; Noora Räsänen; Satu Kaipainen; Ida Hyötyläinen; Hiramani Dhungana; Raisa Giniatullina; Ilkka Ojansuu; Olli Vaurio; Tyrone D. Cannon; Jouko K Lönnqvist; Sebastian Therman; Jaana Suvisaari; Jaakko A. Kaprio; Markku Lähteenvuo; Jussi Tohka; Rashid A. Giniatullin; Claudio Rivera; Iiris Hovatta; Heikki Tanila; Jari Tiihonen; Jari Koıstınaho

doi:10.1101/2020.10.23.350413

NeurosciencebioRxivOct 23, 2020

Preprint

Patient iPSC-astrocytes show transcriptional and functional dysregulation in schizophrenia

Marja Koskuvi iD, Šárka Lehtonen iD, Kalevi Trontti iD, Meike Hedwig Keuters iD, Ying Chieh Wu iD, Hennariikka Koivisto, Anastasia Ludwig iD, L. M. Plotnikova iD, Pekka L. J. Virtanen iD, Noora Räsänen iD, Satu Kaipainen, Ida Hyötyläinen, Hiramani Dhungana iD, Raisa Giniatullina, Ilkka Ojansuu, Olli Vaurio iD, Tyrone D. Cannon iD, Jouko K Lönnqvist iD, Sebastian Therman iD, Jaana Suvisaari iD, Jaakko A. Kaprio iD, Markku Lähteenvuo iD, Jussi Tohka iD, Rashid A. Giniatullin iD, Claudio Rivera iD, , Jari Koıstınaho iD

Abstract

Human astrocytes are multifunctional brain cells and may contribute to the pathophysiology of schizophrenia (SCZ). We differentiated astrocytes from induced pluripotent stem cells of monozygotic twins discordant for SCZ, and found sex-specific gene expression and signaling pathway alterations related particularly to inflammation and synaptic functions. 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 demyelination, synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Altogether, our results show that astrocytes contribute to both familial risk and clinical manifestation of SCZ in a sex-specific manner.

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