Despite substantial progress made toward understanding the molecular changes contributing to autism spectrum disorders (ASD), the neuropathophysiology underlying ASD remains poorly understood1,2. Structural brain imaging in humans is valuable, but lacks resolution at the cellular level. Studies of neuropathology in humans have been hampered by the lack of high quality postmortem brains from individuals with ASD2. For more than decades, mutant mice have served as major tools to dissect the pathophysiology of ASD because of the wealth of molecular and neurobiological techniques developed for studies with rodents. Our knowledge of molecular and cellular mechanisms for ASD is mostly limited to what we have learned from genetically modified mice. However, there are significant evolutionary differences in brain structure and behavior between rodents and humans. For example, social behaviors and the organization of cerebral cortex differ significantly between primates and rodents. The cerebral neocortex comprises ∼80% of the human brain and ∼72% of the macaque brain, but only ∼28% of the rat brain. Prefrontal cortex (PFC), a critical region for high order cognitive and social functions, is under-developed in rodents compared with primates. The unique behavioral features in human ASD have posed significant challenges to assess the translational value of many findings from ASD mouse models. The apparent evolutionary differences in brain structures and behaviors between mouse and human highlight the need of alternative animal models such as non-human primate models for ASD3. The value of a primate model to study ASD has been supported by the generation and characterization of monkeys with altered expressions of MECP2 using the lentivirus- and TALEN-based method4,5.

Mutations in human SHANK3 remain one of the best-replicated and well-characterized genetic defects in ASD. Various types of mutations in SHANK3 have been found in ∼1% of individuals with ASD6. SHANK3 protein is one of the three-member family proteins (SHANK1-3) known to function as postsynaptic scaffolding proteins in excitatory synapses. So far, a total of 14 independent lines of Shank3-mutant mice have been reported, but none of these studies focused on the neuropathology in the prenatal brain6,7. These mutant mice display a spectrum of behavioral phenotypes. However, interpretation of the behavioral phenotypes in rodent models relevant to the SHANK3-related disorders remains a challenge. For these reasons, SHANK3 represented a unique opportunity to test the feasibility of generating an ASD model in non-human primates.

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