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 regulating synaptic transmission and plasticity [1,5].

Shank3 mutant mice exhibit autistic-like behaviors such as impaired social interaction, repetitive behaviors, and self-injurious repetitive grooming, indicating a role of Shank3 in the pathogenesis of autism spectrum disorder (ASD) [1,2,4]. Conditional knockout of Shank3 in the anterior cingulate cortex leads to excitatory synaptic dysfunction and social interaction deficits, while restoring its expression or enhancing the cortex's activity improves social behavior [4]. In addition, Shank3 deficiency in vagal sensory neurons aggravates hypothermia, systemic inflammation, and sepsis mortality in mice [6]. In the heart, ablation of Shank3 in aging mice promotes mitophagy, reduces oxidative stress, and alleviates cardiac dysfunction [3].

In conclusion, Shank3 is essential for normal synaptic function and neuronal connectivity. Its disruption is associated with ASD and other disorders. Studies using Shank3 knockout or conditional knockout mouse models have provided valuable insights into its role in autism-related behaviors, systemic inflammation, and cardiac function during aging.

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. 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/

4. 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/

5. 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/

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/