PONS

Neurons derived from induced pluripotent stem cells (iPSCs) can be used as a relevant, near-patient test system. They are a considerable advance over conventional cellular models used for drug development. Induced pluripotent stem cells derived from fibroblasts of patients with schizophrenia are differentiated into neurons. Drug effects are studied both at the histological level, particularly with respect to modulation of synaptic circuitry, and with respect to changes in transcriptomic and proteomic patterns compared to established animal models.

The lack of availability of relevant cell models is a major reason for fundamental problems in the development of new drugs against diseases of the central nervous system. Neurons from rodents or cells from human brain tumor tissue are often used as models. However, both animal cells and human tumor cells differ significantly from human neurons in their physiology and genetics and do not adequately reproduce their properties. One way out is neurons derived from induced pluripotent stem cells. These are derived by reprogramming from skin fibroblasts and subsequent directed differentiation. The genetic repertoire of patients is contained in these neurons and also enables the analysis of complex, polygenic diseases. In this project, the NMI produces pluripotent stem cells from patients with schizophrenia and differentiates them into neurons for the project partners. Changes in the number of synapses are observed in selected regions of the brain of affected patients.

Therefore, the synaptic circuitry of such neurons is tested in vitro at the NMI and the influence of known and new drugs used to treat previously untreatable negative symptoms of schizophrenia is investigated. In collaboration, the expression patterns of the transcriptome will be determined by high-throughput sequencing and of the proteome by mass spectrometry by the partners. Finally, the results will be compared with parallel analyses performed on the brains of established animal models of schizophrenia.