PhD Scientific Days 2023

Mental Health Sciences II.

Transcriptomic comparison reveals altered neural differentiation and synaptic function in schizophrenia patient-derived iPSC-based hippocampal neurons with ZMYND11 mutation

Text of the abstract

Introduction: Our research group investigates in vitro modeling of neurodevelopmental psychiatric disorders using induced pluripotent stem cells (iPSCs). One of the diseases of interest is schizophrenia, which is characterized by altered brain development and synaptic function. In a previous study, we reprogrammed somatic cells from a schizophrenic patient with a potentially pathogenic de novo mutation in the ZMYND11 gene to iPSCs, and differentiated them into PROX-1 positive hippocampal dentate gyrus granule neurons. Our current understanding suggests that the alteration of hippocampal development may play a pathogenic role in schizophrenia.
Aims: The aim of our study is to investigate whether this ZMYND-11 mutation causes changes in neuronal differentiation resulting in altered gene expression between the patient cell line and isogenic controls.
Methods: We used CRISPR-based genome editing to correct the de novo mutation in the patient cell line and introduced the same mutation into a genetically unrelated healthy control cell line. Next, we differentiated the cells into PROX-1 positive dentate gyrus granule cells and prepared mRNA from the patient cell line and isogenic controls at two different time points during the differentiation process (neural progenitor cells and hippocampal neurons). Using mRNA sequencing we compared the gene expression profile of the mutant cell lines with the wild type in both genetic backgrounds.
Results: At the neural progenitor level, we observed overexpression of genes involved in neural differentiation and underexpression of genes connected to glial function in the mutant lines. At the neuronal level, we found overexpression of genes involved in neural function. Further analysis revealed differentially expressed genes involved in synaptic transmission, particularly in the glutamatergic synapse.
Conclusion: Our study provides evidence that the de novo mutation of the ZMYND11 gene in this specific schizophrenic patient plays a role in nervous system development and synaptic function, and may have contributed to the pathogenesis of schizophrenia.
Funding: NAP 2017-1.2.1-NKP-2017-00002 grant, SE 250+ PhD grant