Striatal cholinergic neurons and L-DOPA induced dyskinesia

描述(申请人提供)：帕金森病(PD)是一种衰弱的疾病，由黑质多巴胺能神经元的进行性退化导致严重的运动功能障碍。L-二羟基苯丙氨酸(L-多巴)治疗可以缓解运动症状，但由于出现异常的不自主运动，即运动障碍，这种药物在慢性治疗中的应用受到限制。了解L多巴对帕金森病患者纹状体内信号转导通路的调节作用，对于设计有效治疗L多巴诱发的运动障碍(LID)具有重要意义。在与LID相关的信号分子中，有细胞外信号调节激酶/丝裂原活化蛋白激酶(ERK)，其在中等刺神经元中的激活与LID的诱导有关。本实验室的初步研究结果表明，长期应用L多巴后，ERK主要在纹状体胆碱能神经元激活，并与LID的表达有关。本研究的目的是确定纹状体胆碱能神经元ERK激活与LID表达的功能意义。我们将在无晶状体小鼠中研究这个问题，这是一种表达LID的黑质纹状体变性的遗传模型，以及已建立的基于单侧神经毒素损伤的模型。拟开展的实验将集中于以下目标：1)纹状体胆碱能神经元运动障碍的时间表达与ERK激活的相关性；2)L多巴诱导纹状体胆碱能神经元和中等棘神经元ERK激活的DA受体亚型和细胞内信号通路的特征；以及3)确定胆碱能神经元ERK激活与神经元兴奋性和胆碱能表型表达的功能结局。更好地了解LID涉及的细胞信号机制将有助于确定治疗帕金森病的潜在靶点。公共卫生意义：L多巴是治疗帕金森氏病(PD)最有效的药物疗法，但长期服用该药物会导致虚弱的异常非自主运动，称为运动障碍。建立能够模拟帕金森病潜在的细胞和行为过程的实验模型，以及L-多巴诱发的运动障碍的发展，对于开发没有不良运动障碍副作用的替代有效的治疗方法是重要的。这里提出的研究将提供关于参与运动障碍行为的细胞信号机制的洞察力，并将有助于确定治疗帕金森病的潜在靶点。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating disorder resulting in severe motor dysfunction caused by progressive degeneration of the substantia nigra dopaminergic neurons. L-dihydroxyphenylalanine (L-DOPA) therapy alleviates the motor symptoms, however the utility of this agent for chronic treatment is limited due to the occurrence of abnormal involuntary movements known as dyskinesia. An understanding of how L-DOPA modulates signaling pathways in the striatum of PD is important in devising an effective treatment for L-DOPA induced dyskinesia (LID). Among the signaling molecules associated with LID is extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK) whose activation in medium spiny neurons has been associated with induction of LID. Preliminary results from our laboratory have shown that ERK is mainly activated in striatal cholinergic neurons with long-term administration of L-DOPA and is correlated with expression of LID. The objective of the proposed studies is to determine the functional significance of ERK activation in striatal cholinergic neurons with respect to the expression of LID. We will examine this issue in aphakia mice, a genetic model of nigrostriatal degeneration that expresses LID, as well as in established unilateral neurotoxin- lesion based models. The proposed experiments are focused on the following objectives: 1) Correlation of the temporal expression of dyskinesia with ERK activation in striatal cholinergic neurons; 2) Characterization of the DA receptor subtype and intracellular signaling pathways linked to L-DOPA-induced ERK activation in striatal cholinergic neurons and medium spiny neurons; and 3) Determining the functional outcome of ERK activation in cholinergic neurons with respect to neuronal excitability and cholinergic phenotypic expression. A better understanding of cell signaling mechanisms involved in LID will facilitate identification of potential targets for the treatment of PD. PUBLIC HEALTH RELEVANCE: L-DOPA is the most efficacious drug therapy for Parkinson's disease (PD), but chronic administration of this drug leads to debilitating abnormal involuntary movements known as dyskinesia. Establishment of experimental models which can mimic the cellular and behavioral processes underlying PD and the development of L-DOPA-induced dyskinesia are important for developing alternative efficacious therapies without unwanted dyskinetic side effects. The research proposed here will provide insight with respect to cell signaling mechanisms involved in dyskinesia behavior and will facilitate identification of potential targets for the treatment of PD.