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Abstract

About one percent of the world's population is suffering from schizophrenia (SCZ), which is a multifactorial neuropsychiatric disorder with high heritability. SCZ is characterized by symptoms such as hallucinations, lack of motivation and memory deficits. On the molecular level, an imbalance of neurotransmitters and changes in the content of synaptic proteins and receptors have been suggested to critically contribute to its pathogenesis. Nonetheless, the underlying molecular causalities of SCZ remain elusive. In this project, out of a small cohort of healthy first-degree relatives and patients suffering from SCZ, one patient was identified to have a heterozygous deletion of chromosome 3q28. After careful consideration of the genetic landscape of this gene locus, I determined two candidate genes encoded on this gene locus: osteocrin (OSTN) and interleukin-1 receptor accessory protein (IL1RAP). While the interleukin-1β (IL-1β) pathway has been previously associated with SCZ, a link between OSTN and SCZ has not been described yet. A recent report revealed that OSTN has been evolutionary repurposed to be expressed in the central nervous system (CNS) exclusively of some anthropoid primates including humans. Interestingly, both, OSTN and IL-1β signaling are described to affect neuronal morphology, by reducing neuronal complexity. In this thesis, an in vitro model of highly pure human induced pluripotent stem cell (hiPSC)-derived cortical neurons was used to study SCZ pathomechanisms in context of a heterozygous 3q28 deletion. Due to its novelty and limited information on OSTN in the brain, I additionally generated an isogenic system where I introduced an OSTN mutation in a healthy control cell line. This is an attempt to reduce genetic complexity and determine contributions of this candidate gene, while the IL-1β pathway was modulated pharmacologically. Transcriptomic analysis of SCZ neurons uncovered that heterozygous 3q28 deletion has a major impact on the expression of genes related to synapses, adhesion molecules and neuronal growth. Morphological characterization of SCZ neurons at d55-60, disclosed a significant increase in neuronal ramification. Moreover, the findings in OSTN mutant neurons confirmed an impact of OSTN on neuronal morphology. Additionally, alterations in density of mature synapses were observed in both systems. These changes were accompanied by altered synaptic activity detected by electrophysiological measurements. Further, modulation of OSTN and IL-1β pathway respectively revealed effects on neuronal ramification. In sum, the presented data strongly suggests a link of the heterozygous 3q28 deletion to neuronal morphology and function in SCZ patients’ neurons. My work endorses hiPSCs as an invaluable model to characterize complex disorders and human-specific aspects, which can help identifying genes that might qualify as molecular targets for therapy in the future.