Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (12): 2711-2719.doi: 10.4103/1673-5374.374654

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Quantitative proteomic and phosphoproteomic analyses of the hippocampus reveal the involvement of NMDAR1 signaling in repetitive mild traumatic brain injury

Zhicheng Tian1, #, Zixuan Cao2, #, Erwan Yang1, #, Juan Li1, Dan Liao1, Fei Wang3, 4, Taozhi Wang3, 5, Zhuoyuan Zhang1, 6, Haofuzi Zhang1, Xiaofan Jiang1, *, Xin Li7, *, Peng Luo1, *#br#   

  1. 1Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China; 2The Sixth Regiment, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi Province, China; 3Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi Province, China; 4Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China; 5Department of Anesthesiology, The Second Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China; 6School of Life Science, Northwest University, Xi’an, Shaanxi Province, China; 7Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
  • Online:2023-12-15 Published:2023-06-15
  • Contact: Peng Luo, MD, pengluo@fmmu.edu.cn; Xin Li, MD, li_xin_mail@126.com; Xiaofan Jiang, MD, jiangxf@fmmu.edu.cn.
  • Supported by:
    This study was funded by the National Natural Science Foundation of China, Nos. 82171363 (to PL), 82171321 (to XL), 82171458 (to XJ); and the Youth Nova Program of Shaanxi, No. 2021KJXX-19 (to PL).

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Abstract: The cumulative damage caused by repetitive mild traumatic brain injury can cause long-term neurodegeneration leading to cognitive impairment. This cognitive impairment is thought to result specifically from damage to the hippocampus. In this study, we detected cognitive impairment in mice 6 weeks after repetitive mild traumatic brain injury using the novel object recognition test and the Morris water maze test. Immunofluorescence staining showed that p-tau expression was increased in the hippocampus after repetitive mild traumatic brain injury. Golgi staining showed a significant decrease in the total density of neuronal dendritic spines in the hippocampus, as well as in the density of mature dendritic spines. To investigate the specific molecular mechanisms underlying cognitive impairment due to hippocampal damage, we performed proteomic and phosphoproteomic analyses of the hippocampus with and without repetitive mild traumatic brain injury. The differentially expressed proteins were mainly enriched in inflammation, immunity, and coagulation, suggesting that non-neuronal cells are involved in the pathological changes that occur in the hippocampus in the chronic stage after repetitive mild traumatic brain injury. In contrast, differentially expressed phosphorylated proteins were mainly enriched in pathways related to neuronal function and structure, which is more consistent with neurodegeneration. We identified N-methyl-D-aspartate receptor 1 as a hub molecule involved in the response to repetitive mild traumatic brain injury , and western blotting showed that, while N-methyl-D-aspartate receptor 1 expression was not altered in the hippocampus after repetitive mild traumatic brain injury, its phosphorylation level was significantly increased, which is consistent with the omics results. Administration of GRP78608, an N-methyl-D-aspartate receptor 1 antagonist, to the hippocampus markedly improved repetitive mild traumatic brain injury-induced cognitive impairment. In conclusion, our findings suggest that N-methyl-D-aspartate receptor 1 signaling in the hippocampus is involved in cognitive impairment in the chronic stage after repetitive mild traumatic brain injury and may be a potential target for intervention and treatment.

Key words: cognitive impairment, Grin1, hippocampus, learning, memory, N-methyl-D-aspartate, N-methyl-D-aspartate receptor 1, phosphoproteomic, proteomic, repetitive mild traumatic brain injury (rmTBI), secondary injury