Extracellular Matrix Dysfunction Drives Synaptic Pathology in Schizophrenia

Schizophrenia is a complex disorder with strong evidence implicating neurodevelopmental abnormalities in its pathophysiology. Olfactory neuroepithelial cells from patients provide a unique platform for studying neurodevelopmental processes. These cells can be cultured into neurospheres and differentiated into neurons, allowing the study of patient-specific alterations related to the disorder. In this study, we utilized olfactory neuroepithelial cells from patients with schizophrenia and controls to explore putative neurodevelopmental dysregulations. RNA-sequencing of neurospheres transcriptome revealed significant alterations in extracellular matrix-related gene expression, suggesting extracellular matrix dysregulation as an underlying contributor to schizophrenia etiopathogenesis.Upon differentiation of olfactory neuroepithelial cells into neurons, transcriptomic analysis identified a significant downregulation of genes involved in synaptic organization and extracellular matrix interactions. To validate these findings, we quantified the protein levels of these genes in olfactory neuroepithelium-derived neurons and in postmortem dorsolateral prefrontal cortex tissue from schizophrenia patients and matched controls. Consistent with our transcriptomic data, schizophrenia subjects exhibited decreased levels of L1CAM, SCG2, and NPTXR proteins. Furthermore, we identified a correlation between the protein levels of L1CAM and NPTXR in the brains of individuals with schizophrenia, a relationship that was absent in control subjects. Our findings provide robust evidence for extracellular matrix and synaptic dysregulation in schizophrenia, linking neurodevelopmental disruptions to molecular alterations in both patient-derived cellular models and postmortem brain. These results underscore the utility of olfactory neuroepithelium cells as a model for studying the neurodevelopmental basis of schizophrenia. They also highlight extracellular matrix-related pathways as potential targets for future search of biomarkers and therapeutic development.