Comprehensive behavioral characterization and impaired hippocampal synaptic transmission in R1117X Shank3 mutant mice
Abstract 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 o...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03505-1 |
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| author | Jingyao Gao Shumin Wu Jingxuan Yang Tong Ye Jie Yang Wenhua Shen Xingwang Chen Li Huang Ruiqi Pang Ping Lin Jiahe Lin Yi Zhou Wei Wang Tao Tan |
| author_facet | Jingyao Gao Shumin Wu Jingxuan Yang Tong Ye Jie Yang Wenhua Shen Xingwang Chen Li Huang Ruiqi Pang Ping Lin Jiahe Lin Yi Zhou Wei Wang Tao Tan |
| author_sort | Jingyao Gao |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-6e9d785e9c374cddb17ec44d6d7e80fe |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-6e9d785e9c374cddb17ec44d6d7e80fe2025-08-20T04:02:41ZengNature Publishing GroupTranslational Psychiatry2158-31882025-08-0115111610.1038/s41398-025-03505-1Comprehensive behavioral characterization and impaired hippocampal synaptic transmission in R1117X Shank3 mutant miceJingyao Gao0Shumin Wu1Jingxuan Yang2Tong Ye3Jie Yang4Wenhua Shen5Xingwang Chen6Li Huang7Ruiqi Pang8Ping Lin9Jiahe Lin10Yi Zhou11Wei Wang12Tao Tan13Oujiang 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 UniversityOujiang 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 UniversityOujiang 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 UniversityOujiang 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 UniversityOujiang 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 UniversityOujiang 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 UniversityOujiang 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 UniversityOujiang 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 UniversityDepartment of Neurobiology, Army Medical UniversityOujiang 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 UniversityOujiang 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 UniversityDepartment of Neurobiology, Army Medical UniversityOujiang 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 UniversityOujiang 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 UniversityAbstract 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.https://doi.org/10.1038/s41398-025-03505-1 |
| spellingShingle | Jingyao Gao Shumin Wu Jingxuan Yang Tong Ye Jie Yang Wenhua Shen Xingwang Chen Li Huang Ruiqi Pang Ping Lin Jiahe Lin Yi Zhou Wei Wang Tao Tan Comprehensive behavioral characterization and impaired hippocampal synaptic transmission in R1117X Shank3 mutant mice Translational Psychiatry |
| title | Comprehensive behavioral characterization and impaired hippocampal synaptic transmission in R1117X Shank3 mutant mice |
| title_full | Comprehensive behavioral characterization and impaired hippocampal synaptic transmission in R1117X Shank3 mutant mice |
| title_fullStr | Comprehensive behavioral characterization and impaired hippocampal synaptic transmission in R1117X Shank3 mutant mice |
| title_full_unstemmed | Comprehensive behavioral characterization and impaired hippocampal synaptic transmission in R1117X Shank3 mutant mice |
| title_short | Comprehensive behavioral characterization and impaired hippocampal synaptic transmission in R1117X Shank3 mutant mice |
| title_sort | comprehensive behavioral characterization and impaired hippocampal synaptic transmission in r1117x shank3 mutant mice |
| url | https://doi.org/10.1038/s41398-025-03505-1 |
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