CRISPR-Edited Macaques Exhibit Autism-Like Behaviors and Brain Abnormalities

Researchers have used gene-editing technology to create macaque monkeys with mutations in the SHANK3 gene, which is linked to autism in humans. The team found that the monkeys exhibited behaviors similar to those seen in humans with autism spectrum disorders, including reduced social interaction, increased repetitive behaviors, anxiety, and sleep disorders. The monkeys also had altered brain structure and connectivity. This study is the first to create monkeys with specific genetic mutations linked to autism, which the researchers said could help them to better understand the condition and develop new treatments.

The researchers used CRISPR-Cas9 gene editing technology to create the monkeys. They chose macaques because they have more complex brains than mice, which are often used in animal studies of autism. The mutations in the SHANK3 gene were precisely targeted and introduced using CRISPR-Cas9, a technique that allows for the modification of specific genes. The resulting monkeys inherited the mutations, indicating the effectiveness of this approach for creating genetically modified primates.

The research team conducted behavioral assessments on the mutant macaques and compared them to normal control macaques. They found that the mutant monkeys had lower overall activity levels, slept less efficiently, and exhibited increased repetitive behaviors. These repetitive behaviors included backflips, finger-licking, and cage biting, and differed from the repetitive scratching behavior commonly observed in mutant mice. Additionally, the mutant macaques showed reduced exploration of their habitat, less vocalization, and decreased social interaction frequencies. Further observations using video presentations revealed abnormal eye movement patterns in the mutant monkeys, including delayed pupil reflexes, extended viewing times, increased lip-smacking behavior, and shortened gaze duration. These abnormal behaviors are highly similar to some behaviors observed in patients with autism spectrum disorder or Phelan-McDermid syndrome.

To investigate the underlying brain changes, the researchers conducted MRI scans on the brains of the mutant macaques. They found that the mutant monkeys had reduced gray matter in their brains, with no change in white matter or cerebrospinal fluid volume. Furthermore, they observed abnormal connections in the brain function of the mutant macaques. For example, some long-range connections between brain regions were reduced, particularly between the default mode network, including the posterior cingulate cortex, medial prefrontal cortex, and motor areas. The thalamus and striatum showed local connection deficits, while the somatosensory cortex, extrastriate cortical areas, and posterior cingulate cortex exhibited local overconnectivity. These findings indicate that the brain structure and function of the mutant macaques exhibit patterns similar to those observed in patients with autism spectrum disorders.

This research provides a valuable new model for studying autism in a species more closely related to humans. The findings contribute to our understanding of the neurological basis of autism and may pave the way for the development of more effective treatments for this complex condition.