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Zhang et al. Ageing Neur Dis 2023;3:24 Ageing and
DOI: 10.20517/and.2023.18
Neurodegenerative
Diseases

Review Open Access

Neuropathological insights from SHANK3 mutant
animal models

Jia-Wei Zhang, Da-Jian He, Xiao-Jiang Li

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration,
Jinan University, Guangzhou 510632, Guangdong, China.
Correspondence to: Da-Jian He, Prof. Xiao-Jiang Li, Guangdong Key Laboratory of Non-human Primate Research, Guangdong-
Hongkong-Macau Institute of CNS Regeneration, Jinan University, Room 301, No. 601 Huangpu Avenue West, Guangzhou
510632, Guangdong, China. E-mail: dajianhe@jnu.edu.cn; xjli33@jnu.edu.cn

How to cite this article: Zhang JW, He DJ, Li XJ. Neuropathological insights from SHANK3 mutant animal models. Ageing Neur
Dis 2023;3:24. https://dx.doi.org/10.20517/and.2023.18

Received: 9 Jun 2023 First Decision: 28 Sep 2023 Revised: 21 Nov 2023 Accepted: 15 Dec 2023 Published: 28 Dec 2023

Academic Editors: Weidong Le, Sofie Hindkjær Lautrup Copy Editor: Dong-Li Li Production Editor: Dong-Li Li

Abstract
SHANK3 is a protein primarily found in the postsynaptic density (PSD) of excitatory synapses in the brain.
Heterozygous mutations in the shank3 gene have been linked to autism spectrum disorder (ASD) and intellectual
disability. There are various animal models carrying mutant SHANK3 that have provided valuable insights into the
pathogenesis of ASD. In this review, we will discuss these animal models, with a specific focus on the
neuropathology observed in shank3 mouse and monkey models. These models are particularly important as they
share closer similarities to humans and are capable of more accurately recapitulating the neuropathological
features observed in individuals with ASD. Mice with mutations in the shank3 gene exhibit deficits in social
behavior, communication, and repetitive behaviors, which are core features of ASD and support the link between
SHANK3 and ASD. However, studies of monkey models with SHANK3 targeting by CRISPR/Cas9 have
demonstrated that, unlike mice with completely knocked-out shank3 genes, the monkey model with complete
deletion of SHANK3 displays a reduction in the number of neuronal cells. This review discusses the species-specific
neuropathology in SHANK3/shank3 knockout mice and monkeys. The differences in neuropathology in SHANK3/
shank3 mutant mouse and monkey models suggest that non-human primate models are highly valuable for
investigating the mechanism of neurodegeneration that may selectively occur in primate brains.

Keywords: CRISPR/Cas9, animal models, SHANK3, neurodegeneration

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
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