Atypical behaviour and connectivity in SHANK3-mutant macaques.

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• SHANK3 gene mutations are a major genetic risk factor for autism spectrum disorder (ASD) and Phelan-McDermid syndrome.
• Non-human primate models offer potential advantages over rodent models for studying ASD phenotypes and treatments.

Purpose of the Study:

• To generate and characterize a non-human primate model of SHANK3 deficiency using CRISPR-Cas9 gene editing.
• To investigate the neural and behavioral consequences of SHANK3 mutations in cynomolgus macaques.

Main Methods:

• CRISPR-Cas9 gene editing was employed to create germline-transmissible SHANK3 mutations in cynomolgus macaques.
• Genotyping, protein analysis, functional magnetic resonance imaging (fMRI), and behavioral assessments were conducted.

Main Results:

• SHANK3 mutations were confirmed in somatic cells and brain tissue, leading to reduced SHANK3 protein levels.
• fMRI revealed altered brain connectivity patterns, indicative of circuit abnormalities.
• Mutant macaques exhibited sleep disturbances, motor deficits, repetitive behaviors, and social and learning impairments.

Conclusions:

• CRISPR-Cas9-mediated SHANK3 mutations in macaques successfully generated a relevant model for ASD and Phelan-McDermid syndrome.
• This primate model recapitulates key genetic, neural, and behavioral features of these conditions.
• The model holds promise for advancing the understanding and treatment of SHANK3-associated neurodevelopmental disorders.