# Mutant Shank3 macaque monkeys for neurobiological studies of ASD

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $225,900

## Abstract

PROJECT SUMMARY/ABSTRACT
 The ability to genetically modify the mouse genome has revolutionized biomedical research. However,
its impact on our understanding of brain disorders is limited partially due to the inherent differences in the
structure and physiology of the brain between rodents and humans. Most notably, the prefrontal cortex is one
of the largest and most developed portions of the human brain and a top candidate for pathological processes
in many psychiatric disorders. Yet, rodents have only a rudimentary prefrontal cortex and are thus limited in
exhibiting the complex cognitive functions that are mediated by this region. The lack of predictive animal
models is now considered one of the key bottlenecks in developing effective treatments for brain disorders.
 Non-human primates are much more closely related to humans than are rodents, and this is reflected in
their brain development, structure and physiology. Hence, it is increasingly recognized that they provide an
attractive model to study higher brain function and brain disorders. The recent development of highly efficient
CRISPR genome-editing technology made it feasible to directly manipulate the genome in zygotes, thus
expanding genetic manipulations to many species including non-human primates.
 In the past 4 years, we have been collaborating with a team of scientists in the Brain Cognition and
Brain Disease Institute, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences to
use CRISPR/Cas9 to generate macaque monkey models of monogenic ASD. We have now successfully
generated Shank3 mutant cynomolgus macaques. Shank3 is a glutamatergic postsynaptic scaffolding protein
critical for synapse development and function. Heterozygous mutations of the Shank3 gene in humans lead to
Phelan-McDermid syndrome (PMS), an autism spectrum disorder. Initial characterization of the 5 founder
Shank3 mutant monkeys revealed sleep disturbances, motor deficits, and increased repetitive behaviors, as
well as social and learning impairments. Unbiased analysis of fMRI data showed altered local and global
connectivity patterns indicative of circuit abnormalities. Together, these results parallel some aspects of the
gene-circuit-behavior dysfunction in human ASD and PMS. Here we propose, in collaboration with our
colleagues in SIAT, China, to generate F1 generation of Shank3 mutant monkeys to validate initial
observations, to further behavioral and neurophysiological characterization and to bring mutant sperms to US
for establishing a colony for sharing with autism research community.

## Key facts

- **NIH application ID:** 9879438
- **Project number:** 1R01MH121802-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Robert Desimone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $225,900
- **Award type:** 1
- **Project period:** 2020-04-07 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879438

## Citation

> US National Institutes of Health, RePORTER application 9879438, Mutant Shank3 macaque monkeys for neurobiological studies of ASD (1R01MH121802-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9879438. Licensed CC0.

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