Bridging the Scales via Personalized Cellular Modeling and Deep Phenotyping in Schizophrenia

Do synaptic deficits in patient-derived neurons predict individual differences in brain circuitry and cognitive impairment in schizophrenia (SCZ)?In a multiscale framework integrating magnetic resonance imaging, electroencephalography, and cognitive data from more than 500 participants with in vitro phenotyping of donor-matched induced pluripotent stem cell (iPSC)–derived neurons, reduced excitatory synapse density and transcriptomic signatures predicted the individual alterations in brain structure, electrophysiology, and cognition in vivo, providing a mechanistic link from synapse deficits to cognitive impairments in SCZ.This study establishes a patient-specific bridge from synapse biology to the individual clinical phenotype, offering a road map for mechanism-based target and drug discovery.

Corresponding Author: Florian J. Raabe, MD, PhD, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany (florian_raabe@psych.mpg.de); Michael J. Ziller, PhD, Department of Psychiatry, University of Münster, 48149 Münster, Germany (ziller@uni-muenster.de).

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