Bridging the scales: leveraging personalized disease models and deep phenotyping to dissect cognitive impairment in schizophrenia

Schizophrenia (SCZ) is a highly heritable brain disorder marked by a wide range of changes throughout the central nervous system. These changes include alterations at the molecular and cellular levels, suggesting significant disruptions in synapse function, as well as modifications in brain structure and activity. However, it remains unclear, how changes in molecular synapse biology translate into neurophysiological and ultimately behavioral consequences across scales. Here, we narrow this translational gap in contemporary biological psychiatry by establishing a generalizable framework to bridge the scales and pinpoint biological mechanisms underlying individual psychiatric symptoms. We show that genetically driven changes in neuronal gene expression and a resulting reduction in excitatory synaptic density in vitro are linked to alterations of brain structure, electrophysiology and ultimately cognitive function in vivo. These results provide a direct connection between the molecular origins of synapse reduction in SCZ and its neurobiological and phenotypic consequences on the individual patient level, paving the way to develop new mechanism informed treatment options.