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Yue Qin, Yasong Du, Liqiang Chen, Yanyan Liu, Wenjing Xu, Ying Liu, Ying Li, Jing Leng, et al.
(2022).
A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling.
Molecular Psychiatry, 27(7), 2985-2998.
Springer Science and Business Media LLC.
- Publication date
-
6 Apr 2022
- Identifier
-
10.1038/s41380-022-01539-1
- Authors
-
Yue Qin,
Yasong Du,
Liqiang Chen,
Yanyan Liu,
Wenjing Xu,
Ying Liu,
Ying Li,
Jing Leng,
Yalan Wang,
Xiao-Yong Zhang,
Jianfeng Feng,
Feng Zhang,
Li Jin,
Zilong Qiu,
Xiaohong Gong,
Hongyan Wang
- Source
- Molecular Psychiatry
- Details
- 27(7), 2985-2998
- Reference type
- article
- Publisher
- Springer Science and Business Media LLC
- Metadata source
- crossref
Abstract
Abstract The genetic etiology and underlying mechanism of autism spectrum disorder (ASD) remain elusive. SHANK family genes (SHANK1/2/3 ) are well known ASD-related genes. However, little is known about how SHANK missense mutations contribute to ASD. Here, we aimed to clarify the molecular mechanism of and the multilevel neuropathological features induced by Shank1 mutations in knock-in (KI) mice. In this study, by sequencing the SHANK1 gene in a cohort of 615 ASD patients and 503 controls, we identified an ASD-specific recurrent missense mutation, c.2621 G > A (p.R874H). This mutation demonstrated strong pathogenic potential in in vitro experiments, and we generated the corresponding Shank1 R882H-KI mice. Shank1 R882H-KI mice displayed core symptoms of ASD, namely, social disability and repetitive behaviors, without confounding comorbidities of abnormal motor function and heightened anxiety. Brain structural changes in the frontal cortex, hippocampus and cerebellar cortex were observed in Shank1 R882H-KI mice via structural magnetic resonance imaging. These key brain regions also showed severe and consistent downregulation of mGluR1-IP3R1-calcium signaling, which subsequently affected the release of intracellular calcium. Corresponding cellular structural and functional changes were present in Shank1 R882H-KI mice, including decreased spine size, reduced spine density, abnormal morphology of postsynaptic densities, and impaired hippocampal long-term potentiation and basal excitatory transmission. These findings demonstrate the causative role of SHANK1 in ASD and elucidate the underlying biological mechanism of core symptoms of ASD. We also provide a reliable model of ASD with core symptoms for future studies, such as biomarker identification and therapeutic intervention studies.
Study authors in this cited reference