Atypical Behaviour and Connectivity in SHANK3-Mutant Macaques

Abstract

Mutation or disruption of the SHANK3 (SH3 domain and ankyrin repeat) gene represents a highly penetrant, monogenic risk-factor for Autism Spectrum Disorder (ASD) and is a cause of Phelan–McDermid syndrome (PMS). Recent advances in gene editing have enabled the creation of genetically engineered non-human primate (NHPs) models, which might better approximate the behavioral and neural abnormalities of ASD than rodent models and lead to more effective treatments. Here, we report CRISPR/Cas9-mediated generation of germline transmissible cynomolgus macaques and their F1 offspring carrying SHANK3 mutations. Genotyping of somatic cells and brain biopsies confirmed mutations in the SHANK3 gene and reduced SHANK3 proteins. Analysis of fMRI data revealed altered local and global connectivity patterns indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits, and increased repetitive behaviors, as well as social and learning impairments. Together, these results parallel some aspects of the gene-circuit-behavior dysfunction in human ASD and PMS.