Deletion of CNTNAP2 Gene Leads to Dendritic Spine Abnormalities in Familial Schizophrenia: Insights from induced Pluripotent Stem Cells-Derived Patients’ Neurons

Schizophrenia, a complex neuropsychiatric disorder, exhibits a wide range of genetic diversity. Multiple Genome-wide studies have identified several Copy Number Variations (CNVs) associated with Schizophrenia. One of the significant CNVs, comprising an intragenic deletion of the CNTNAP2 gene, has been associated with various neuro-developmental and neuro-psychiatric disorders. However, the molecular mechanism leading to the pathogenesis of Schizophrenia remained unclear. In this study, we report a 7q35-36.1del encompassing the entire CNTNAP2 gene in two affected siblings. Human induced Pluripotent Stem Cells (hiPSCs) were generated from both affected individuals. Neurons derived from the patient's hiPSCs lines have revealed that the dendritic length & arborization, spine number & density, soma area & volume were decreased in the patient’s neurons, while axon length was increased. Further classifying the dendritic spines, it was observed that the percentage of filopodia spines was increased, whereas stubby, mushroom and long thin spines were decreased in the patient’s neurons. Transcriptomics of hiPSCs-derived neurons has revealed eight significant dysregulation genes that interact directly or indirectly with CNTNAP2. Of these eight genes, Schizophrenia associated genes, PADI2 and LHX2 were observed to be significantly dysregulated. Overall, this study has identified abnormalities in neuronal architecture in hiPSCs-derived patients’ neurons harbouring CNTNAP2 gene deletion, confirming the disease pathophysiology of Schizophrenia.