From the Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, China (Liu, Xue, Sun, C. Tang); the Department of Neurology, the Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu, China (Zhou); the Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and the Second People's Hospital of Huai'an, Jiangsu, China (Y. Tang).
From the Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, China (Liu, Xue, Sun, C. Tang); the Department of Neurology, the Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu, China (Zhou); the Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and the Second People's Hospital of Huai'an, Jiangsu, China (Y. Tang)
J Psychiatry Neurosci. 2024 Feb 1;49(1):E23-E34. doi: 10.1503/jpn.230079. Print 2024 Jan-Feb.
Depression is a prevalent nonmotor symptom in Parkinson disease and can greatly reduce the quality of life for patients; the dopamine receptors found in glutamatergic pyramidal cells in the medial prefrontal cortex (mPFC) play a role in regulating local field activity, which in turn affects behavioural and mood disorders. Given research showing that glial cell-derived neurotrophic factor (GDNF) may have an antidepressant effect, we sought to evaluate the impact of exogenous GDNF on depression-like behaviour in mouse models of Parkinson disease.
We used an established subacute model of Parkinson disease in mice involving intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by brain stereotaxic injection of GDNF into the mPFC region. Subsequently, we assessed depression-like behaviour using the sucrose preference test, forced swimming test and tail suspension test, while also evaluating protein expression in the mPFC.
We included 60 mice, divided into 3 groups, including a control group (saline injection), an MPTP plus saline injection group and an MPTP plus GDNF injection group. We found that exogenous GDNF injection into the mPFC led to an increase in dopamine receptor D1 (DRD1) protein levels. We also observed that activating the protein kinase A pathway through DRD1 produced a prolonged antidepressant response. Under GDNF stimulation, the expression of dopamine receptor D2 (DRD2) remained constant, suggesting that the DRD2 signal was ineffective in alleviating depression-like symptoms. Moreover, our investigation involved Golgi staining and Western blot techniques, which found enhanced synaptic plasticity, including increased dendritic branches, dendritic spines and retrograde protection after GDNF treatment in Parkinson disease models.
A subtle motor phenotype became evident only toward the conclusion of the behavioural testing period. The study exclusively involved male mice, and no separate control group receiving only GDNF treatment was included in the experimental design.
Our findings support a positive effect of exogenous GDNF on synaptic plasticity, mediated by DRD1 signalling in the mPFC, which could facilitate depression remission in Parkinson disease.
抑郁症是帕金森病中一种常见的非运动症状，会极大地降低患者的生活质量；在大脑前额叶皮质（mPFC）的谷氨酸能锥体神经元中发现的多巴胺受体在调节局部场活动中发挥作用，进而影响行为和情绪障碍。鉴于研究表明胶质细胞衍生的神经营养因子（GDNF）可能具有抗抑郁作用，我们试图评估外源性 GDNF 对帕金森病小鼠模型中抑郁样行为的影响。
我们使用已建立的帕金森病亚急性模型，通过腹腔注射 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），然后将 GDNF 脑立体定向注射到 mPFC 区域。随后，我们使用蔗糖偏好测试、强迫游泳测试和悬尾测试评估抑郁样行为，同时评估 mPFC 中的蛋白质表达。
我们纳入了 60 只小鼠，分为 3 组，包括对照组（生理盐水注射）、MPTP 加生理盐水注射组和 MPTP 加 GDNF 注射组。我们发现，mPFC 中外源性 GDNF 注射导致多巴胺受体 D1（DRD1）蛋白水平增加。我们还观察到，通过 DRD1 激活蛋白激酶 A 途径产生了延长的抗抑郁反应。在 GDNF 刺激下，多巴胺受体 D2（DRD2）的表达保持不变，表明 DRD2 信号无效缓解抑郁样症状。此外，我们的研究涉及 Golgi 染色和 Western blot 技术，发现 GDNF 治疗后帕金森病模型中的突触可塑性增强，包括树突分支、树突棘和逆行保护增加。
只有在行为测试期结束时才会出现微妙的运动表型。该研究仅涉及雄性小鼠，实验设计中没有单独的仅接受 GDNF 治疗的对照组。
我们的研究结果支持外源性 GDNF 通过 mPFC 中的 DRD1 信号对突触可塑性产生积极影响，这可能有助于帕金森病中的抑郁缓解。
