中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 1107-1117.doi: 10.4103/1673-5374.355816

• 原著:退行性病与再生 • 上一篇    下一篇

前额叶皮质中胶质细胞系源性神经营养因子减少可引起帕金森病认知障碍

  

  • 出版日期:2023-05-15 发布日期:2022-11-01
  • 基金资助:
    中国国家自然科学基金项目（81971006，82101263）；江苏省青年科学基金项目（BK20210903）；徐州医科大学人才研究基金项目（RC20552114）；徐州市科技计划项目（KC19016）；徐州医科大学项目（2018KJ06）

Blunt dopamine transmission due to decreased GDNF in the PFC evokes cognitive impairment in Parkinson’s disease

Chuan-Xi Tang1, #, Jing Chen2, #, Kai-Quan Shao1, Ye-Hao Liu1, Xiao-Yu Zhou1, 3, Cheng-Cheng Ma1, Meng-Ting Liu4, Ming-Yu Shi1, 5, Piniel Alphayo Kambey1, Wei Wang6, Abiola Abdulrahman Ayanlaja1, Yi-Fang Liu1, Wei Xu1, Gang Chen5, Jiao Wu1, Xue Li7, Dian-Shuai Gao1, *#br#   

  1. 1Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  2Experinental Teaching Center of Morphology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  3Department of Neurology, Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu Province, China; 4Department of Rehabilitation, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  5Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  6Department of Medicine, Jiangnan University, Wuxi, Jiangsu Province, China;  7Department of Nursing Care, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
  • Online:2023-05-15 Published:2022-11-01
  • Contact: Dian-Shuai Gao, PhD, gds@xzhmu.edu.cn.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, Nos. 81971006 (to DSG), 82101263 (to CXT); Jiangsu Province Science Foundation for Youths, No. BK20210903 (to CXT); Research Foundation for Talented Scholars of Xuzhou Medical University, No. RC20552114 (to CXT); Science & Technology Program of Xuzhou, No. KC19016 (to JC); and Project of Xuzhou Medical University, No. 2018KJ06 (to JC).

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摘要：

有研究发现胶质细胞源性神经营养因子缺失可能是帕金森病的主要危险因素；但尚无确定胶质细胞源性神经营养因子与帕金森病认知表现之间的潜在关系的研究。因此首先于2018年9月至2020年1月在徐州医科大学附属医院进行了一项回顾性病例对照研究，发现血清中胶质细胞系源性神经营养因子含量降低是帕金森病伴认知障碍发生的危险因素。进而以1-甲基-4-苯基-1，2，3，6-四氢吡啶诱导建立帕金森病小鼠模型，分析前额叶皮质中胶质细胞系源性神经营养因子、多巴胺传递和认知功能的潜在关系。结果表明，前额叶皮质中胶质细胞系源性神经营养因子减少可通过多巴胺能突触前膜多巴胺转运蛋白的表达，来削弱多巴胺释放及传递作用，进而导致锥体神经元树突棘的缺失和退化，进而导致认知障碍的发生。磁共振成像结果也显示胶质细胞系源性神经营养因子的长期缺乏可造成降低前额叶皮质与其他脑区连通性。而外源性胶质细胞系源性神经营养因子可有效改善上述表现。提示前额叶皮质中胶质细胞系源性神经营养因子减少，可导致包含突触连接和神经回路的神经可塑性退化，进而引发帕金森病认知障碍。

http://orcid.org/0000-0001-8567-0238 (Dian-Shuai Gao)

关键词: 帕金森病, 胶质细胞系源性神经营养因子, 前额叶皮质, 多巴胺传递, 度中心性, 认知障碍, 多巴胺转运体, 树突棘, 突触可塑性

Abstract: Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease.

Key words: cognitive impairment, degree centrality, dendritic spine, dopamine transmission, dopamine transporter, glial cell line-derived neurotrophic factor, Parkinson’s disease, prefrontal cortex, synaptic plasticity