Shank3, also known as SH3 and multiple ankyrin repeat domain protein 3, is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. It plays crucial roles in synapse formation, maturation, and maintenance, and is involved in various biological processes related to neural function [1,6].

Shank3 mutant mice have been instrumental in understanding its functions. Shank3 gene-deleted mice show autistic-like behaviors such as self-injurious repetitive grooming and social interaction deficits, uncovering defects at striatal synapses and cortico-striatal circuits [2]. Conditional knockout of Shank3 in the anterior cingulate cortex leads to excitatory synaptic dysfunction and social interaction deficits in mice, while restoration of SHANK3 expression in this area improves social behavior [5]. In the context of cerebral ischemia/reperfusion, conditional knockout of Shank3 in neurons aggravates neuronal injuries, and Shank3 protects against oxidative stress and inflammation through interacting with STIM1 [3]. In aging mice, cardiac-specific conditional knockout of Shank3 promotes mitophagy, reduces oxidative stress, and alleviates cardiac dysfunction [4]. Homozygous and heterozygous Shank3 deficiency in mice aggravates hypothermia, systemic inflammation, and sepsis mortality, and specific deletion of Shank3 in Nav1.8-expressing sensory neurons recapitulates these deficits [7]. In a Shank3 mouse model of ASD, thalamocortical neuron hyperexcitability is observed, causally linked to HCN2 channelopathy, and restoring HCN2 function ameliorates sensory and sleep problems [8].

In conclusion, Shank3 is essential for normal synaptic function and neural development. Studies using gene knockout and conditional knockout mouse models have revealed its significant roles in autism-related behaviors, neuronal injury response, cardiac function during aging, body temperature and inflammation regulation, and thalamocortical circuit function, providing valuable insights into the mechanisms of related diseases [1-5,7,9].

References:

1. Uchino, Shigeo, Waga, Chikako. 2012. SHANK3 as an autism spectrum disorder-associated gene. In Brain & development, 35, 106-10. doi:10.1016/j.braindev.2012.05.013. https://pubmed.ncbi.nlm.nih.gov/22749736/

2. Peça, João, Feliciano, Cátia, Ting, Jonathan T, Fu, Zhanyan, Feng, Guoping. 2011. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. In Nature, 472, 437-42. doi:10.1038/nature09965. https://pubmed.ncbi.nlm.nih.gov/21423165/

3. Zhang, Hongchen, Feng, Yuan, Si, Yanfang, Zhang, Lei, Li, Xia. 2023. Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation. In Redox biology, 69, 102983. doi:10.1016/j.redox.2023.102983. https://pubmed.ncbi.nlm.nih.gov/38064762/

4. Wang, Ying, Xu, Yuerong, Guo, Wangang, Li, Yan, Zhang, Mingming. 2022. Ablation of Shank3 alleviates cardiac dysfunction in aging mice by promoting CaMKII activation and Parkin-mediated mitophagy. In Redox biology, 58, 102537. doi:10.1016/j.redox.2022.102537. https://pubmed.ncbi.nlm.nih.gov/36436456/

5. Guo, Baolin, Chen, Jing, Chen, Qian, Wang, Wenting, Wu, Shengxi. 2019. Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice. In Nature neuroscience, 22, 1223-1234. doi:10.1038/s41593-019-0445-9. https://pubmed.ncbi.nlm.nih.gov/31332372/

6. Huang, Min, Qi, Qi, Xu, Tao. 2023. Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review. In Frontiers in molecular neuroscience, 16, 1128974. doi:10.3389/fnmol.2023.1128974. https://pubmed.ncbi.nlm.nih.gov/36846568/

7. Zhang, Linlin, Bang, Sangsu, He, Qianru, Jiang, Yong-Hui, Ji, Ru-Rong. 2023. SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis. In Frontiers in immunology, 14, 1124356. doi:10.3389/fimmu.2023.1124356. https://pubmed.ncbi.nlm.nih.gov/36845137/

8. Guo, Baolin, Liu, Tiaotiao, Choi, Soonwook, Wu, Shengxi, Fu, Zhanyan. 2024. Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice. In Cell reports. Medicine, 5, 101534. doi:10.1016/j.xcrm.2024.101534. https://pubmed.ncbi.nlm.nih.gov/38670100/