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Dopamine neurotransmission in a model of DOPA-responsive dystonia

多巴反应性肌张力障碍模型中的多巴胺神经传递

基本信息

批准号：
9481589
负责人：
ELLEN J. HESS
金额：
$ 3万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9481589
关键词：
Address Adult Affect Anatomy Architecture Behavior Behavioral Biological Assay Brain Cells Childhood Childhood Onset Dystonias Chronic DRD2 gene Data Defect Dendrites Development Disease Dopa-Responsive Dystonia Dopamine Dopamine Agonists Dopamine D1 Receptor Dopamine Receptor Dystonia Dystonic Disorder Electron Microscopy Exhibits Functional disorder Genes Glutamates Human Knock-in Mouse Knowledge Lead Levodopa Life Measures Mediating Membrane Metabolism Modeling Morphology Movement Mus Muscle Contraction Mutation Nature Neurologic Neurons Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Patients Pharmacology Phenocopy Physiological Physiology Posture Process Property Residual state Role Severities Signal Pathway Signal Transduction Slice Smooth Muscle Symptoms Synapses Testing Time Tyrosine 3-Monooxygenase Vertebral column deprivation experimental study insight interdisciplinary approach monoamine mouse model nerve supply neurochemistry neurotransmission novel therapeutics patch clamp postsynaptic presynaptic prototype public health relevance receptor reconstruction response restoration transmission process treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Abnormal dopamine (DA) neurotransmission is consistently observed across many different forms of dystonia, but the DA defects that give rise to dystonia are poorly understood. L-DOPA-responsive dystonia (DRD) is considered a prototype disorder for understanding how abnormal DA neurotransmission evokes dystonia. DRD is characterized by childhood onset dystonia with diurnal fluctuation whereby symptoms worsen throughout the course of the day. The distinguishing feature of DRD is the dramatic improvement in symptoms after restoration of DA signaling with L-DOPA or DA agonists. Indeed, DRD is caused by mutations in genes critical for DA synthesis, including tyrosine hydroxylase (TH). DRD-causing TH mutations are associated with some residual TH activity whereas mutations that abolish TH activity cause childhood parkinsonism suggesting that TH activity and [DA] are critical determinants in the development of dystonia. However, the nature of the DA signaling dysfunction that gives rise to dystonia is unknown. To address this gap in our knowledge, we generated a knockin mouse bearing the human DRD-causing Q381K mutation in TH (DRD mice). Like the human disorder, DRD mice display reduced TH activity, a reduction in [DA], dystonic movements that worsen throughout the course of the active period and improvement in the dystonia in response to L-DOPA. Thus, DRD mice exhibit the core neurochemical and symptomatic features of human DRD, thereby providing us with the unprecedented opportunity to dissect the mechanisms underlying DRD from gene to behavior. Our preliminary data demonstrate that the dystonia is mediated by [DA] that is <1% of normal. A similar reduction in presynaptic DA in adults would cause parkinsonism. Therefore, divergent postsynaptic responses likely account for the differences in the neurological consequences of reduced DA transmission between Parkinson's disease (PD) and dystonia. Indeed, our preliminary data demonstrate D1R supersensitivity, hyperexcitability of medium spiny neurons (MSNs), a reduction in MSN dendrite number and abnormal corticostriatal innervation. Therefore, we will test the hypothesis that early life DA deficiency in combination with (mal)adaptive postsynaptic responses gives rise to dystonia by using a multidisciplinary approach to examine the pre- and postsynaptic consequences of reduced DA transmission associated with dystonia. The Specific Aims are: 1. To elucidate the relationship between monoamine metabolism and the severity of dystonia. 2. To determine the DA receptor subtype(s) and signaling defects that contribute to the dystonia. 3. To delineate alterations in th intrinsic and synaptic properties of D1 and D2R-expressing MSNs. 4. To examine the dendritic morphology and ultrastructural changes in corticostriatal synapses onto D1R and D2R-expressing MSNs in response to early-life DA deprivation in DRD mice.

描述(申请人提供)：肌张力障碍的特征是不自主的肌肉收缩，导致虚弱的扭转动作和姿势。在许多不同形式的肌张力障碍中都可以观察到异常的多巴胺(DA)神经传递，但导致肌张力障碍的DA缺陷却知之甚少。L多巴反应性肌张力障碍被认为是理解多巴胺神经传递异常引起肌张力障碍的一个原型疾病。DRD的特点是儿童期出现肌张力障碍，并有昼夜波动，症状在一天中恶化。多巴酚丁胺或多巴胺激动剂恢复DA信号后，DRD的症状明显改善。事实上，DRD是由对DA合成至关重要的基因突变引起的，包括酪氨酸羟基酶(TH)。导致DRD的TH突变与一些残留的TH活性有关，而取消TH活性的突变会导致儿童帕金森病，这表明TH活性和[DA]是肌张力障碍发生的关键决定因素。然而，导致肌张力障碍的DA信号功能障碍的性质尚不清楚。为了解决我们知识中的这一差距，我们培育了一只携带人类DRD导致TH(DRD小鼠)Q381K突变的敲击小鼠。与人类疾病一样，DRD小鼠表现出TH活性降低，[DA]减少，肌张力障碍运动在整个活动期恶化，以及对L-多巴的反应改善肌张力障碍。因此，DRD小鼠表现出人类DRD的核心神经化学和症状特征，从而为我们提供了前所未有的机会来剖析DRD从基因到行为的潜在机制。我们的初步数据表明，肌张力障碍是由[DA]调节的，即正常值的1%。成年人突触前多巴胺的类似减少也会导致帕金森症。因此，不同的突触后反应可能解释了帕金森病(PD)和肌张力障碍之间DA传递减少的神经学后果的差异。事实上，我们的初步数据显示，D1R超敏、中等棘神经元(MSN)的超兴奋性、MSN树突数量减少和皮质纹状体神经异常支配。因此，我们将使用多学科的方法来检验早期生命DA缺乏与(MAL)适应性突触后反应共同导致肌张力障碍的假说，以检验与肌张力障碍相关的DA传递减少在突触前和突触后的后果。其具体目的是：1.阐明单胺代谢与肌张力障碍严重程度的关系。2.确定导致肌张力障碍的DA受体亚型(S)和信号缺陷。3.观察表达D1R和D2R的MSN的TH固有特性和突触特性的变化。4.观察DRD小鼠早期DA剥夺对D1R和D2R阳性神经元突触的树突形态和超微结构的影响。