Lähteenvuo, M. | bioRxiv Science

bioRxiv2020

Patient iPSC-astrocytes show transcriptional and functional dysregulation in schizophrenia

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.

neuroscience↗

bioRxiv2020

Molecular signaling pathways underlying schizophrenia

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. Studies using stem cell-derived neurons have investigated differentially expressed genes (DEGs) and GO and KEGG pathways between patients and controls, but not analyzed data-driven causal molecular pathways involved. We used Ingenuity Pathway Analysis (IPA) to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. In contrast, no dopamine-specific genes were consistently involved. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA -related pathway, compared to those time periods when the same individual did not use the drug. This association was not attributable to general adherence to drug treatments. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA -related purine, oxidative stress, and glutamatergic signaling pathways are primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists - which have shown beneficial effects in an experimental Adcyap1-/- mouse model for schizophrenia - could be potential treatments before the full manifestation of illness involving dopaminergic abnormalities.

neuroscience↗