Association of cognitive deficit with glutamate and insulin signaling in a rat model of Parkinson's disease

Cognitive deficit is a frequent non-motor symptom in Parkinson 's disease (PD) with an unclear pathogenesis. Recent research indicates possible involvement of insulin resistance and glutamate excitotoxicity in PD development. We investigated cognitive performance and the brain glutamate and insulin signaling in a rat model of PD induced by bilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA). Cognitive functions were assessed with Passive avoidance (PA) and Morris Water Maze (MWM) tests. The expression of tyrosine hydroxylase (TH) and proteins involved in insulin (IR, pI3K, ERK) and glutamate receptor (AMPAR, NMDAR) signaling was assessed in the hippocampus (HPC), hypothalamus (HPT) and striatum (S) by immunofluorescence, Western blot and ELISA. Three months after 6-OHDA treatment, cognitive deficit was accompanied by decreased AMPAR activity and TH levels (HPC, S), while levels of the proteins involved in insulin signaling remained largely unchanged. Spearman’s rank correlation revealed a strong positive correlation for pAMPAR-PA (S), pNMDAR-pI3K (HPC) and pNMDAR-IR (all regions). Additionally, a positive correlation was found for TH-ERK and TH-pI3K, and a negative one for TH-MWM/errors and pI3K-MWM/time (S). These results suggest a possible association between brain glutamate (but not insulin) signaling dysfunction and cognitive deficit in a rat PD model, detected three months after 6-OHDA treatement.

认知功能障碍是帕金森病（Parkinson's disease, PD）常见的非运动症状，但其发病机制尚未明确。近期研究表明，胰岛素抵抗与谷氨酸兴奋性毒性可能参与帕金森病的发生发展。本研究针对双侧纹状体内注射6-羟基多巴胺（6-hydroxydopamine, 6-OHDA）构建的帕金森病大鼠模型，探究了其认知表现以及脑内谷氨酸与胰岛素信号通路的变化。认知功能通过避暗实验（Passive avoidance, PA）与莫里斯水迷宫（Morris Water Maze, MWM）进行评估。研究人员采用免疫荧光、蛋白质印迹（Western blot）及酶联免疫吸附测定（ELISA）技术，在海马（hippocampus, HPC）、下丘脑（hypothalamus, HPT）与纹状体（striatum, S）中检测了酪氨酸羟化酶（tyrosine hydroxylase, TH），以及参与胰岛素信号通路（胰岛素受体IR、磷酸肌醇3-激酶pI3K、细胞外调节蛋白激酶ERK）和谷氨酸受体信号通路（AMPA受体AMPAR、NMDA受体NMDAR）的相关蛋白表达水平。6-羟基多巴胺造模3个月后，模型大鼠出现认知功能障碍，同时海马与纹状体内AMPA受体活性及酪氨酸羟化酶水平均显著下降，而胰岛素信号通路相关蛋白水平整体未发生明显变化。斯皮尔曼等级相关分析显示：纹状体内磷酸化AMPA受体（pAMPAR）与避暗实验评分、海马内磷酸化NMDA受体（pNMDAR）与pI3K水平、以及各检测脑区的pNMDAR与IR水平均呈显著正相关。此外，酪氨酸羟化酶与ERK、pI3K水平呈正相关；纹状体内TH水平与莫里斯水迷宫错误数、pI3K水平与莫里斯水迷宫逃避时间呈负相关。本研究结果提示，在6-羟基多巴胺造模3个月后的帕金森病大鼠模型中，脑内谷氨酸信号通路功能异常（而非胰岛素信号通路）或与认知功能障碍存在密切关联。