Reactivating a schizophrenia risk gene-enriched prefrontal ensemble suppresses decision noise

Schizophrenia genetics and single-cell transcriptomics implicate prefrontal excitatory neurons and synaptic programs, but how these vulnerabilities alter circuit dynamics, behavior, and pharmacological targetability remains unclear. We identify a clozapine-responsive prefrontal ensemble enriched for schizophrenia risk genes that stabilizes value-guided choice. NMDA receptor hypofunction increased value-independent decision noise and weakened the ensemble’s pre-choice transient, while clozapine rescued both. Chemogenetic inhibition of the ensemble increased decision noise, demonstrating causality. By integrating receptor affinities with mouse and human single-cell transcriptomes, we designed a rational multi-receptor antagonist cocktail that reactivated the ensemble and rescued decision noise without increasing NREM sleep time or NREM delta power, in contrast to clozapine. These findings link schizophrenia genetics to cortical ensemble dynamics and establish ensemble-targeted pharmacology as a strategy for ameliorating pathological computations.