Striatal cholinergic neurons and L-DOPA induced dyskinesia

描述（由申请人提供）：帕金森病（PD）是一种使人衰弱的疾病，由黑质多巴胺能神经元的进行性变性引起严重的运动功能障碍。L-二羟基苯丙氨酸（L-DOPA）治疗减轻了运动症状，然而，由于发生称为运动障碍的异常不自主运动，该药剂用于慢性治疗的效用受到限制。了解左旋多巴如何调节帕金森病纹状体中的信号通路对于设计左旋多巴诱导的运动障碍（LID）的有效治疗是重要的。在与LID相关的信号传导分子中，有细胞外信号调节激酶/促分裂原活化蛋白激酶（ERK），其在中型棘神经元中的活化与LID的诱导相关。我们实验室的初步结果表明，ERK主要在长期给予L-DOPA的纹状体胆碱能神经元中被激活，并且与LID的表达相关。本研究的目的是确定ERK激活在纹状体胆碱能神经元中与LID表达相关的功能意义。我们将在无晶状体小鼠（一种表达LID的黑质纹状体变性的遗传模型）以及已建立的单侧神经毒素损伤模型中研究这个问题。本研究的主要目的是：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）纹状体胆碱能神经元和中型棘状神经元多巴胺受体亚型和ERK激活相关的细胞内信号通路的特征;和3）确定胆碱能神经元中ERK激活的功能结果与神经元兴奋性和胆碱能表型表达的关系。更好地理解参与LID的细胞信号传导机制将有助于确定治疗PD的潜在靶点。公共卫生相关性：左旋多巴是治疗帕金森病最有效的药物，但长期服用这种药物会导致虚弱的异常不自主运动，称为运动障碍。建立能够模拟PD潜在的细胞和行为过程以及L-DOPA诱导的运动障碍的发展的实验模型对于开发没有不希望的运动障碍副作用的替代有效疗法是重要的。本文提出的研究将提供关于涉及运动障碍行为的细胞信号传导机制的见解，并将有助于确定治疗PD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.