PROJECT SUMMARY The degree of cognitive impairment is the best predictor of functional outcomes in schizophrenia, but the efficacious treatment of these deficits remains a significant challenge. Genome-wide association and exome sequencing studies point to an essential role for components of the Arc protein complex in glutamatergic dysregulation in schizophrenia. Studies of synaptic plasticity and memory consolidation suggest that loss of Arc function may be important in the pathophysiology of cognitive impairments in multiple neuropsychiatric disorders. These results indicate that targeting Arc may provide a new avenue to improve cognitive impairments in these disease contexts. To explore the feasibility of this objective, we carried out a high-throughput, image-based screen in mouse cortical neurons to identify small molecules that potentiated neuronal activity-dependent induction of Arc at the mRNA and protein level. One of the strongest enhancers of Arc expression was an atypical antipsychotic, lurasidone, whereas many other antipsychotics were inactive. Consistent with the potential unique properties of lurasidone, human clinical studies suggest that lurasidone can improve cognitive performance in schizophrenia. Moreover, in preclinical behavioral studies, lurasidone ameliorates the learning and memory impairment induced by the NMDA receptor antagonist MK-801. Based on these observations, we hypothesize that differential modulation of Arc in cortical glutamatergic neurons by lurasidone is the basis for its pro-cognitive effects. We will test this hypothesis by first deriving a quantitative structure-activity relationship that allows for the optimization of Arc enhancement using our chemical synthesis and high-content neuronal imaging platform. Building on our strong preliminary data demonstrating the conservation of lurasidone’s enhancement of Arc expression in human iPSC-derived cortical neurons and lurasidone’s ability to increase dendritic spine density deficits in these neurons, we will profile a focused collection of lurasidone derivatives with strong preliminary data demonstrating the feasibility of successfully doing so. To extend this functional characterization, we will use cerebral organoids from existing schizophrenia and matched healthy iPSCs to determine their response to Arc-enhancing compounds at the level of single-cell transcriptomes, dendritic spine density, and electrophysiological profiles using multielectrode array technology. Finally, to connect to clinical studies, systematic characterization of iPSC-derived neurons from our existing cohort of first-episode schizophrenia patients who show significant cognitive improvement with lurasidone compared to patients who are lurasidone non-responders will be performed to provide mechanistic insights into Arc and cellular phenotypes that correlate with cognitive enhancement and differential patient response. Successful completion of these studies will result in a more precise un...