Atypical behaviour and connectivity in SHANK3-mutant macaques

Mutation or disruption of the SH3 and ankyrin repeat domains 3 ( SHANK3 ) gene represents a highly penetrant, monogenic risk factor for autism spectrum disorder, and is a cause of Phelan–McDermid syndrome. Recent advances in gene editing have enabled the creation of genetically engineered non-human-primate models, which might better approximate the behavioural and neural phenotypes of autism spectrum disorder than do rodent models, and may lead to more effective treatments. Here we report CRISPR–Cas9-mediated generation of germline-transmissible mutations of SHANK3 in cynomolgus macaques ( Macaca fascicularis ) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the SHANK3 gene and reduced levels of SHANK3 protein in these macaques. Analysis of data from functional magnetic resonance imaging revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits and increased repetitive behaviours, as well as social and learning impairments. Together, these results parallel some aspects of the dysfunctions in the SHANK3 gene and circuits, as well as the behavioural phenotypes, that characterize autism spectrum disorder and Phelan–McDermid syndrome. The CRISPR–Cas9-mediated generation of germline-transmissible mutations of SHANK3 in cynomolgus macaques ( Macaca fascicularis ) forms the basis of a non-human-primate model of autism spectrum disorder and Phelan–McDermid syndrome.