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.
Highlights
Schizophrenia (SZ) is a serious disease with a prevalence of 1% and high social burden[1,2]
All patients and healthy controls were investigated by the Scale for the Assessment of Negative Symptoms (SANS)[21], brief psychiatric rating scale (BPRS)[22], Hamilton Depression Rating Scale (HDRS)[23], and Modified Simpson Angus Scale (MSAS; EPS)[24]
Our results suggest that examination of calcium signalling and analysis of transcriptome profiles may provide a mean to discriminate among healthy controls, schizophrenia, and autism samples in Human induced pluripotent stem cells (hiPSC)-based models of different neurodevelopmental disorders
Summary
Schizophrenia (SZ) is a serious disease with a prevalence of 1% and high social burden[1,2]. HiPSC-derived neurons from healthy control individuals as well as from patients with SZ and autism were tested in a panel of assays, including quantification of synaptic markers, measurement of neurite outgrowth, analysis of calcium signals as well as transcriptome analysis. Significant differences were only observed for the autism group compared with healthy controls (Supplementary Fig. S5).
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