DISC1 mutant macaques capture behavioral and neural hallmarks of psychiatric disease.

Schizophrenia is a devastating and complex neurological disorder with poorly understood neurodevelopmental origins. Current rodent models often fail to fully capture human symptomology, hindering therapeutic development. We generated a germline-transmissible DISC1 mutant model in cynomolgus macaques using CRISPR-Cas9 targeting of exon 9. F0 founders and their F1 heterozygous offspring displayed increased stereotypic behaviors and self-injury, reduced exploration, social withdrawal, and sleep fragmentation. Fluoxetine partially ameliorated these behaviors in one founder. Neuroimaging revealed enlarged dorsal striatum (suggesting dopaminergic hyperfunction) and reduced medial amygdala (associated with emotional dysregulation). Plasma metabolomics indicated elevated dopamine and 3-methoxytyramine alongside decreased serotonin metabolite hydroxyindoleacetic acid (HIAA). Notably, one mosaic male exhibited enhanced visual precision and aberrant multisensory integration. Single-nuclei RNA sequencing of the dorsolateral prefrontal cortex revealed an excitatory/inhibitory imbalance-specifically, reduced parvalbumin-positive interneurons and synaptic dysregulation-accompanied by downregulation of autism-risk genes. These macaques recapitulate key psychiatric phenotypes including social deficits, aggression and anxiety, providing a valuable model for screening and testing of targeted therapeutics.