Grundwald LM1, Stock R1, Haag K1, Buckenmaier S2, Eberle MC3, Wildgruber D3, Storchak H3, Kriebel M1, Weißgraeber S4, Mathew L4, Singh Y4, Loos M5, Li KW6, Kraushaar U2, Fallgatter AJ3, Volkmer H7
Abstract
Human induced pluripotent stem cells (hiPSC) provide an attractive tool to study disease mechanisms of neurodevelopmental disorders such as schizophrenia. A pertinent problem is the development of hiPSC-based assays to discriminate schizophrenia (SZ) from autism spectrum disorder (ASD) models. Healthy control individuals as well as patients with SZ and ASD were examined by a panel of diagnostic tests. Subsequently, skin biopsies were taken for the generation, differentiation, and testing of hiPSC-derived neurons from all individuals. SZ and ASD neurons share a reduced capacity for cortical differentiation as shown by quantitative analysis of the synaptic marker PSD95 and neurite outgrowth. By contrast, pattern analysis of calcium signals turned out to discriminate among healthy control, schizophrenia, and autism samples. Schizophrenia neurons displayed decreased peak frequency accompanied by increased peak areas, while autism neurons showed a slight decrease in peak amplitudes. For further analysis of the schizophrenia phenotype, transcriptome analyses revealed a clear discrimination among schizophrenia, autism, and healthy controls based on differentially expressed genes. However, considerable differences were still evident among schizophrenia patients under inspection. For one individual with schizophrenia, expression analysis revealed deregulation of genes associated with the major histocompatibility complex class II (MHC class II) presentation pathway. Interestingly, antipsychotic treatment of healthy control neurons also increased MHC class II expression. In conclusion, transcriptome analysis combined with pattern analysis of calcium signals appeared as a tool to discriminate between SZ and ASD phenotypes in vitro.
- Department Molecular Biology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany.
- Department Cell Physiology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany.
- Department of Psychiatry, University of Tübingen, Osianderstrasse 24, 72076, Tübingen, Germany.
- CeGaT GmbH – Center for Genomics and Transcriptomics, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.
- Sylics (Synaptologics BV), PO Box 71033, 1008 BA, Amsterdam, The Netherlands.
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands.
- Department Molecular Biology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany. volkmer@nmi.de.