Dissecting neuronal hyperexcitability in Schizophrenia using induced pluripotent stem cells

• Applicant: Professor Dr. Michael J. Ziller
• Subject Area: Biological Psychiatry ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506248983

Psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BD) are among the major public health burdens. Despite tremendous success in identifying large numbers of common genetic variants associated with these highly heritable conditions, little progress has been made in translating these associations into an understanding of the underlying molecular and cellular mechanisms. This lack of insight is to some extend reflected in the stalled development of novel antipsychotic drugs since more than 30 years, leaving between 30-50% of patients without effective treatment. These difficulties are partially rooted in the highly polygenic architecture of SCZ and BD, where many common genetic variants of small effect act together to drive alterations in molecular and cellular endophenotypes over the course of brain development and beyond. Here, we aim to address this challenge and identify altered cellular endophenotypes along with their causal molecular drivers in polygenic SCZ. To that end, we will leverage induced pluripotent stem cells (iPSCs) from patients with SCZ to capture their polygenic disease architecture in disease-relevant neuronal cell types in vitro. In particular, we have discovered changes in the excitability of iPSC-derived mature cortical neurons from patients with SCZ as a genetically encoded cellular endophenotype. Moreover, we have identified a differentially expressed candidate gene, LRP1, that is likely contributing to the observed hyperexcitability of patient-specific iPSC-derived neurons. Against this background, we hypothesize that specific common risk variants in SCZ act in concert in cis and trans to alter gene expression or splicing patterns of LRP1 as a hub gene in SCZ, causing changes the excitability pattern of cortical excitatory neurons. Here we propose to test this hypothesis and to define the precise molecular mechanism which causes the hyperexcitability phenotype of iPSC derived neurons from SCZ patients. To that end, we will pursue an integrative approach combining functional genomics, human post mortem brain research, induced pluripotent stem cell technology as well as cell biology approaches. In particular, we will to: (i) Validate and characterize the observed LRP1 gene expression in iPSC derived neurons and human post mortem brain, (ii) dissect the regulation of LRP1 transcriptional control in iPSC derived neurons and (iii) determine the functional impact of LRP1 de-regulation on neuronal excitability. In its entirety, these studies will establish cortical hyperexcitability as a polygenetic driven cellular endophenotype contributing to polygenic pathophysiology in SCZ. Moreover, this research agenda will for the first time provide support for the hub gene concept and establish a firm causal link between common polygenically driven altered gene expression patterns and defined changes in cellular endophenotypes in SCZ.

• DFG Programme: Research Grants