iPSC-derived cortical neurons from patients with schizophrenia exhibit changes in early neuronal development

Abstract

One percent of the world population suffers from the neurodevelopmental disorder schizophrenia. During the last years, above hundreds of risk genes and functional changes in glutamatergic, GABAergic and dopaminergic signalling have been identified. Furthermore, prenatal complications increase the risk to develop schizophrenia. First symptoms occur between puberty and early adolescence and are divided into positive, negative and cognitive symptoms. Until today no suitable cellular test system has been developed to study the disease background and treatment opportunities. The development of iPSC technology enables the investigation of schizophrenia related changes based on patient-derived cells. In this thesis, fibroblast derived from healthy and disease individuals were reprogrammed into iPSC and further differentiated into cortical neurons. Each developmental step starting as iPSC and resulting as neurons showed the same morphological properties independent from the donor. Despite these similarities changes in early neurodevelopmental processes were observed in iPSC-derived neurons from patients with schizophrenia. The neurite outgrowth, the PSD95 cluster density and the calcium flux were reduced in case of schizophrenia. Transcriptome analysis revealed changes in gene expression related to gene of neuronal development, synapse, calcium signalling and immune response. In increased expression of MHCII related genes was measured via transcriptome analysis and immunocytochemical staining in cells from patients witch schizophrenia. Additionally, the effect of the antipsychotics clozapine, haloperidol and olanzapine as well as the mimetic peptides narpin, neurexide and FN4-NF3 on neurite outgrowth were investigated. A significantly reduced neurite outgrowth was observed in iPSC-derived neurons from CTR 1 after treatment with haloperidol or olanzapine. Above mentioned characteristics of cortical neurons cells exhibited similarities to previously described primary cells from patients with schizophrenia. Based on these findings iPSC-derived neurons could be used as test system for basic research and for the development of new therapeutical approaches for neurodevelopmental diseases like schizophrenia.