The retina as a window to investigate synaptic dysfunction in schizophrenia

Schizophrenia is characterized by synaptic dysfunction; however, there remains a critical need for individualized assessment of synaptic disturbances. We integrate a multi-scale approache to bridge molecular, cellular, circuit-level, and clinical domains. Using multimodal deep phenotyping in the CDP/MIMICSS cohort (N > 700), we identify retinal microstructural and functional alterations—particularly in the inner plexiform layer (IPL)—via optical coherence tomography (OCT) and electroretinography (ERG), reflecting shared synaptic pathology with the brain. These retinal changes correlate with clinical severity and individual genetic risk. Complementarily, iPSC-derived neurons from patients reveal disrupted synaptic gene expression, driven by aberrant alternative polyadenylation (APA). Crucially, iPSC-derived molecular and functional readouts predict individual variability in cognition, brain structure, and EEG signatures—demonstrating high translational potential. Our work establishes the retina as a non-invasive window into central synaptic pathology, with potential for patient stratification, and positions iPSC models as powerful tools for mechanistic insight. Together, these approaches pave the way for precision psychiatry—enabling personalized stratification, and molecular dissection of diseases mechnism.