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Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium collected from FXS hiPSC\u2010derived astrocyte cultures and correlated inversely with intracellular Ca<jats:sup>2+<\/jats:sup> responses to activation of L\u2010type voltage\u2010gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase\u2010C\u03b31 (PLC\u03b31), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS\u2010specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)\u2010responsive astrocyte population. To conclude, our studies identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.<\/jats:p>","DOI":"10.1002\/glia.24080","type":"journal-article","created":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T12:37:02Z","timestamp":1629808622000},"page":"2947-2962","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome"],"prefix":"10.1002","volume":"69","author":[{"given":"Ulla\u2010Kaisa","family":"Peteri","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine University of Helsinki  Helsinki 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