Striatal cholinergic neurons and L-DOPA induced dyskinesia

纹状体胆碱能神经元和左旋多巴诱导的运动障碍

• 批准号: 8693110
• 负责人: Un Jung Kang
• 金额: $ 28.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693110
• 关键词: Acute; Adverse effects; Animals; Area; Attenuated; Behavior; Behavioral; Biochemical; CREB1 gene; Cells; Choline O-Acetyltransferase; Chronic; Complement; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DARPP; Data; Development; Disease; Disease model; Dopa; Dopamine; Dopamine D1 Receptor; Dyskinetic syndrome; ELK1 gene; Experimental Models; Figs - dietary; Functional disorder; Genetic; Genetic Models; Interneurons; Investigation; L-DOPA induced dyskinesia; Laboratories; Lesion; Link; Mediating; Messenger RNA; Metabolic; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Motor; Mus; Muscarinic M1 Receptor; Neurons; Neurotoxins; Oxidopamine; Parkinson Disease; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphorylation; Physiological; Process; Proteins; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Substantia nigra structure; Symptoms; Testing; Tissues; Translations; abnormal involuntary movement; aphakia mice; base; cholinergic; cholinergic neuron; clinical practice; cytochrome c oxidase; dopaminergic neuron; effective therapy; functional outcomes; genetic manipulation; insight; mitogen and stress-activated protein kinase 1; neuronal excitability; new therapeutic target; novel; patch clamp; public health relevance; receptor; receptor function; research study; response; Acute; Adverse effects; Animals; Area; Attenuated; Behavior; Behavioral; Biochemical; CREB1 gene; Cells; Choline O-Acetyltransferase; Chronic; Complement; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DARPP; Data; Development; Disease; Disease model; Dopa; Dopamine; Dopamine D1 Receptor; Dyskinetic syndrome; ELK1 gene; Experimental Models; Figs - dietary; Functional disorder; Genetic; Genetic Models; Interneurons; Investigation; L-DOPA induced dyskinesia; Laboratories; Lesion; Link; Mediating; Messenger RNA; Metabolic; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Motor; Mus; Muscarinic M1 Receptor; Neurons; Neurotoxins; Oxidopamine; Parkinson Disease; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphorylation; Physiological; Process; Proteins; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Substantia nigra structure; Symptoms; Testing; Tissues; Translations; abnormal involuntary movement; aphakia mice; base; cholinergic; cholinergic neuron; clinical practice; cytochrome c oxidase; dopaminergic neuron; effective therapy; functional outcomes; genetic manipulation; insight; mitogen and stress-activated protein kinase 1; neuronal excitability; new therapeutic target; novel; patch clamp; public health relevance; receptor; receptor function; research study; response

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.

描述（由申请人提供）：帕金森氏病（PD）是一种使人衰弱的疾病，导致严重的运动功能障碍是由黑质尼格拉多巴胺能神经元进行性变性引起的。 l-二羟基苯基丙氨酸（L-DOPA）疗法减轻运动症状，但是由于异常的非自愿运动称为屈服不良运动，该药物对慢性治疗的实用性受到限制。对L-DOPA如何调节PD纹状体中的信号通路的理解对于设计有效治疗L-DOPA诱导的运动障碍（LID）很重要。在与盖子相关的信号分子中，有细胞信号调节激酶/有丝分裂原激活的蛋白激酶（ERK），其在中棘神经元中的激活与盖子的诱导有关。我们实验室的初步结果表明，ERK主要在长期施用L-DOPA的纹状体胆碱能神经元中激活，并且与LID的表达相关。拟议的研究的目的是确定纹状体胆碱能神经元中ERK激活相对于lid表达的功能意义。我们将在Aphakia小鼠中研究这个问题，Aphakia小鼠是一种表达盖子的斑纹纹状体变性的遗传模型，以及已建立的基于单侧神经毒素模型的遗传模型。提出的实验集中在以下目标上：1）纹状体胆碱能神经元中运动障碍与ERK激活的时间表达相关； 2）表征DA受体亚型和细胞内信号传导途径与L-DOPA诱导的ERK激活相关的纹状体胆碱能神经元和中刺神经元的激活； 3）根据神经元兴奋性和胆碱能表型表达，确定胆碱能神经元中ERK激活的功能结果。更好地理解盖子涉及的细胞信号传导机制将有助于鉴定PD治疗的潜在靶标。公共卫生相关性：L-DOPA是帕金森氏病（PD）的最有效的药物治疗，但是这种药物的长期给药会导致衰弱的异常非自愿运动，称为Dykenesia。建立可以模仿PD的细胞和行为过程的实验模型以及L-DOPA诱导的运动障碍的发展对于开发而没有不必要的性质副作用而开发替代性有效疗法很重要。此处提出的研究将提供有关运动障碍行为涉及的细胞信号传导机制的见解，并将促进鉴定PD治疗的潜在靶标。