Shank3, a member of the Shank family proteins, 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. Five CpG-islands have been identified in the Shank3 gene, and its tissue-specific expression is epigenetically regulated by DNA methylation [1].

Shank3 mutant mice, including gene knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in revealing its functions. Shank3-deficient mice exhibit autistic-like behaviors such as impaired social interaction, repetitive behaviors, and self-injurious repetitive grooming, indicating its involvement in the pathogenesis of autism spectrum disorder (ASD) [1,2,5]. In addition, Shank3 mutant mice show striatal synapse and cortico-striatal circuit defects [2], as well as anterior cingulate cortex dysfunction underlying social deficits [5]. In cerebral ischemia/reperfusion, conditional knockout of Shank3 in neurons aggravates neuronal injuries, suggesting its protective role against oxidative stress and inflammation [3]. In the heart, ablation of Shank3 in aging mice alleviates cardiac dysfunction by promoting CaMKII activation and Parkin-mediated mitophagy [4]. Also, Shank3 deficiency in vagal sensory neurons of mice aggravates hypothermia, systemic inflammation, and sepsis mortality [6].

In conclusion, Shank3 is essential for normal synaptic function and neuronal connectivity. Studies using Shank3 KO/CKO mouse models have significantly contributed to understanding its roles in diseases like ASD, cerebral ischemia/reperfusion injury, cardiac aging, and systemic inflammation. These findings provide insights into the biological mechanisms and potential therapeutic targets related to these disease conditions.

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. 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/