CRISPR-Cas9 Gene Editing Creates Primate Model for Autism Spectrum Disorders

Researchers have successfully created a primate model of autism using CRISPR gene editing technology. The team used this technique to edit specific sites on the SHANK3 gene in macaques and successfully bred SHANK3 mutant macaques. They also bred the first-generation offspring with SHANK3 mutations using the sperm of mutant macaques. Somatic cell genotyping and brain tissue biopsy showed the mutation of the SHANK3 gene and a decrease in SHANK3 protein levels.

The SHANK3 gene encodes a scaffolding protein on excitatory synapses, which coordinates the response of cells to signals from presynaptic cells by organizing other proteins on the postsynaptic cell membrane. Abnormalities in this gene have been associated with various diseases, and studies have shown that a single mutation in the SHANK3 gene can cause disease. Over 1% of congenital autism spectrum disorders are caused by single SHANK3 gene mutations.

To investigate whether SHANK3 mutant macaques exhibit autism-related abnormal behaviours, the research team conducted a series of behavioural assessments on mutant macaques and normal control macaques. They found that the overall activity level of mutant macaques was significantly lower, and the time required to fall asleep was significantly longer, with more frequent awakenings during sleep. They also found that the repetitive stereotyped behaviours of mutant macaques increased significantly, including backflips, finger-licking, and cage biting. Furthermore, mutant macaques showed a tendency to explore their habitat less, with significantly reduced vocalizations and social interaction frequencies.

The team also investigated whether SHANK3 mutant macaques had abnormal brain structure and functional connections. They found that the brain structure of mutant macaques showed reduced gray matter, with no change in white matter and cerebrospinal fluid volume. Additionally, they found abnormal connections in the brain function of mutant macaques. For example, some long-range connections between brain regions were reduced, especially between the default mode network, including the posterior cingulate cortex, medial prefrontal, and motor areas. Furthermore, the thalamus and striatum showed local connection deficits, while the somatosensory cortex, extrastriate cortical areas, and posterior cingulate cortex showed local overconnectivity.

These abnormal behaviours and brain structure and function of mutant macaques are highly similar to some behaviours of autism spectrum disorder or Phelan-McDermid syndrome patients. The study suggests that CRISPR gene editing technology can efficiently mutate macaque genes, and the mutation can be inherited. The primate model of autism could help researchers better understand the effects of SHANK3 gene mutations and develop new treatments for autism spectrum disorders.