Comparative characterization of human induced pluripotent stem cells (hiPSC) derived from patients with schizophrenia and autism

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.

Mental health dished up—the use of iPSC models in neuropsychiatric research

“…A further problem is that of sample heterogeneity, with iPSCs generated from different subtypes of SCZ shown to demonstrate differential results, for example in undifferentiated (Brennand et al 2011) versus paranoid SCZ (Robicsek et al 2013). This has also been observed in SCZ iPSCs derived from treatment-responsive versus treatment-resistant patients (Grunwald et al 2019;Nakazawa et al 2017;Paulsen et al 2012). Moreover, patient genetic background has been found to have opposing effects on miRNA expression (Ahmad et al 2018).…”

Investigation of de novo mutations in a schizophrenia case-parent trio by induced pluripotent stem cell based in vitro disease-modeling: Convergence of schizophrenia and autism-related cellular phenotypes

“…Both the increased NPC proliferation and accelerated neurite outgrowth are phenotypes that were previously associated with ASD, however in the investigated SZ trio, they could also be identi ed. Grunwald et al (47) used iPSC-based methodology to make head-to-head comparisons between SZ and ASD-derived neural cells, and also found overlapping phenotypes, however it was possible to discriminate SZ and AD-derived neurons by the combination of transcriptome analysis and Ca 2+ imaging.…”

The potential of induced pluripotent stem cells for discriminating neurodevelopmental disorders

“…52,53 Accordingly, iPSC-derived cortical neurons showed a reduction in neuronal connectivity, neurite outgrowth, and synaptic markers (PSD-95, glutamate receptors) in idiopathic SZ. 25,[54][55][56] Reduced synaptogenesis was also shown for dopaminergic neurons and cortical interneurons. 57 Likewise, deficits in hippocampal neurogenesis were reported for dentate gyrus granule neurons accompanied by reduced neurotransmitter release and neuronal activity.…”

“…In contrast to limited data sets for SZ transcriptomes, six publications have compared transcriptome data of iPSC-derived neurons from idiopathic ASD to healthy controls (Table 1). 25,[28][29][30][31][32] For example, ATP8A1 is a catalytic component of a P4-ATPase flippase complex and involved in cell migration. Compared to controls, elevated ATP8A1 protein was found in the hippocampus and temporal lobe of juvenile autistic subjects.…”