Gao Jingyao, Wu Shumin, Yang Jingxuan, Ye Tong, Yang Jie, Shen Wenhua, Chen Xingwang, Huang Li, Pang Ruiqi, Lin Ping, Lin Jiahe, Zhou Yi, Wang Wei, Tan Tao
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, P. R. China.
Department of Neurobiology, Army Medical University, Chongqing, 400038, China.
Transl Psychiatry. 2025 Aug 9;15(1):274. doi: 10.1038/s41398-025-03505-1.
Mutations in the Shank3 gene are strongly associated with various neurodevelopmental disorders, particularly autism spectrum disorder (ASD). The R1117X mutation, which results in truncated SHANK3 protein, has been implicated in dysfunctions in the striatum and cortex. However, its effects on hippocampal function remain poorly understood. In this study, we performed a comprehensive behavioral and synaptic analysis of homozygous R1117X Shank3 mutant mice. These mice exhibited deficits in sensory gating, motor coordination, and pain perception, alongside severe anxiety in novel environment. Additionally, they showed significant impairments in learning and memory, as well as abnormal spontaneous fine motor behaviors. Histological analysis revealed morphological changes in the hippocampus, which were coupled with deficits in synaptic transmission and plasticity. Notably, we observed a downregulation of glutamatergic receptors in the hippocampus, particularly NMDA receptor subtypes. Taken together, these findings demonstrate that the homozygous R1117X Shank3 mutant mouse represents a valuable model for investigating schizophrenia associated with intellectual disability. The altered hippocampal morphology, impaired synaptic function, and deficits in learning and memory observed in this model provide new insights into the underlying mechanisms of Shank3-related neurodevelopmental disorders.
Shank3基因的突变与多种神经发育障碍密切相关，尤其是自闭症谱系障碍（ASD）。导致截短的SHANK3蛋白的R1117X突变与纹状体和皮质功能障碍有关。然而，其对海马体功能的影响仍知之甚少。在本研究中，我们对纯合R1117X Shank3突变小鼠进行了全面的行为和突触分析。这些小鼠在感觉门控、运动协调和疼痛感知方面存在缺陷，同时在新环境中表现出严重焦虑。此外，它们在学习和记忆方面表现出显著损伤，以及异常的自发精细运动行为。组织学分析揭示了海马体的形态变化，这与突触传递和可塑性的缺陷相关。值得注意的是，我们观察到海马体中谷氨酸能受体的下调，尤其是NMDA受体亚型。综上所述，这些发现表明纯合R1117X Shank3突变小鼠是研究与智力残疾相关的精神分裂症的有价值模型。在该模型中观察到的海马体形态改变、突触功能受损以及学习和记忆缺陷，为Shank3相关神经发育障碍的潜在机制提供了新的见解。
