帕金森病伴工作记忆障碍（PD-WMD）因机制不明而缺乏有效治疗，严重影响患者生活质量。申请者前期观察到，PD-WMD患者血清胶质细胞系源性神经营养因子（GDNF）减少；拮抗小鼠前额叶皮质（PFC）的GDNF作用可致工作记忆障碍，已知PFC执行工作记忆的前提是多巴胺（DA）兴奋突触后的谷氨酸（Glu）能锥体神经元。有文献报道，GDNF可抑制突触前膜多巴胺转运体（DAT）对胞外DA的重摄取作用。故推测，在PD患者PFC：GDNF含量降低，引发DA能突触前膜DAT作用增强、突触后Glu能锥体神经元活动减弱等，最终致工作记忆障碍。本项目拟，在明确PD-WMD与PFC的GDNF含量下降密切关联的基础上，证实：PFC的GDNF含量降低，依次引发DA能突触前膜DAT分布增多/DAT二聚体减少、胞外DA减少、突触后Glu能锥体神经元兴奋性传递减弱，致工作记忆障碍。本项目也为研究脑高级功能提供理论依据。

Parkinson disease with working memory disorder (PD-WMD) remains a holy-grail of neurodegenerative diseases which is the research focus of contemporary cognitive science and neuropsychopathology. .In the prefrontal cortex (PFC) of PD-WMD patients, there is decreased dopamine (DA) in the extracellular space. DA activates glutamatergic pyramidal neurons in PFC, which is a prerequisite for working memory. In our preliminary research, Glial cell line-derived neurotrophic factor (GDNF) in the serum of PD-WMD patients was significantly decreased, and blocking the effect of GDNF in the PFC of mice contributes to working memory disorder. Other studies have confirmed that GDNF inhibits the effect of dopamine transporter (DAT) in the presynaptic membrane, leading to increased DA in the synaptic cleft. Therefore, we hypothesize that PD-WMD may occur due to the decreased GDNF in the PFC, and this may lead to the over-promotion of DAT effect. Subsequently, the decrease of DA transmission, and the suppressed activity of postsynaptic glutamatergic pyramidal neurons leading to the occurrence of working memory disorder..To address these questions, the explicit relationship between decreased GDNF in the PFC and working memory disorder of PD-WMD patients will be determined firstly according to clinical case-control study. Then, we will further probe whether the decreased GDNF in the PFC resulted in increased distribution/decreased dimerization of DAT in presynaptic membrane; decreased DA in the extracellular space; decreased excitability and projection activity of postsynaptic glutamatergic pyramidal cells; and subsequent working memory disorder. From all of the above, we could clarify the implication of decreased GDNF in the PFC leading to PD-WMD and elucidate the related neural networks of glutamatergic pyramidal cells..This project will reveal the effects of abnormal DA transmission and the mechanism involved as it initiates PD-WMD, providing a theoretical basis for further exploration of the mechanisms driving advanced brain function.