Author:
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
Abstract
AbstractHuman 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
5 articles.
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