A primate resource for autism research

See allHide authors and affiliations

Science Translational Medicine  10 Jul 2019:
Vol. 11, Issue 500, eaay3571
DOI: 10.1126/scitranslmed.aay3571


A macaque model of SHANK3 mutation exhibits neurological phenotypes similar to patients with autism and Phelan-McDermid Syndrome.

The prevalence of autism in the US and UK population is greater than 1%, yet there are currently no available therapeutics that target the underlying pathology. The rise of rodent models targeting identified risk genes for autism has generated a renewed interest in the search for a pharmacological therapy. However, the spectrum of behavioral disturbances associated with autism have been difficult to model in rodents that display clear differences in cognitive and social strategies. Additionally, the development of biomarkers using resting-state functional magnetic resonance imaging (MRI) has been difficult to adapt to preclinical rodent models. To tackle these problems, Zhou et al. have created a primate model of autism by introducing germline mutations in the SHANK3 gene of macaques (Macaca fascicularis) using CRISPR-Cas9 genetic editing. Mutations in SHANK3 are frequently associated with the development of autism and the neurodevelopmental disorder Phelan-McDermid Syndrome (PMS). Using a battery of behavioral tests, the authors show that macaques with SHANK3 mutations exhibit multiple behavioral phenotypes reminiscent of patients with autism or PMS. These include severe sleep disturbances, increased stereotypic behavior, impaired social interaction, and reduced vocalization. In addition, video-based eye tracking revealed alterations in pupillary reflex and gaze fixation that are seen in children that develop autism. Together, the results suggest the SHANK3 mutant macaque model will be a valuable resource for modelling the disruptions in complex brain function seen in autism. Moreover, examination of SHANK3 mutants using resting-state functional MRI revealed alterations in global and local brain connectivity that may be useful as a preclinical biomarker.

The development of primate models such as the SHANK3 mutant macaque is an advancement that may improve the predictive value of autism models. Now researchers can use this model to test the impact of potential therapeutic strategies on more complex behavioral symptoms and identify treatment-sensitive biomarkers that can be used for clinical trials. The main limitation of the study is a relatively small sample size that is likely due to the cost of creating and housing primate models. Although further studies are needed to determine the true advantages of using this macaque model, it is likely that primate models will accelerate autism research and enable the identification of more effective therapeutic strategies.

Highlighted Article

View Abstract

Navigate This Article