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：
8887950
负责人：
ELLEN J. HESS
金额：
$ 33.92万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887950
关键词：
Accounting Address Adult Affect Architecture Behavior Behavioral Biological Assay Brain Cells Childhood Childhood Onset Dystonias Chronic DRD2 gene Data Defect Dendrites Development Disease Dopamine Dopamine Agonists Dopamine D1 Receptor Dopamine Receptor Dystonia Dystonic Disorder Electron Microscopy Exhibits Functional disorder Genes Glutamates Human Knowledge Lead Life Measures Mediating Membrane Metabolism Modeling Morphology Movement Mus Muscle Contraction Mutation Nature Neurologic Neurons Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Patients 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 insight interdisciplinary approach monoamine mouse model nerve supply neurochemistry neurotransmission novel therapeutics patch clamp postsynaptic presynaptic prototype public health relevance receptor reconstruction research study 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（由申请人提供）：肌张力障碍的特征是不自主的肌肉收缩，导致令人衰弱的扭转运动和姿势。在许多不同形式的肌张力障碍中都观察到异常的多巴胺（DA）神经传递，但引起肌张力障碍的 DA 缺陷却知之甚少。 L-DOPA 反应性肌张力障碍 (DRD) 被认为是了解异常 DA 神经传递如何诱发儿童肌张力障碍的原型疾病。具有昼间波动的肌张力障碍，其中症状在一天中恶化，DRD 的显着特征是用 L-DOPA 或 DA 激动剂恢复 DA 信号后症状显着改善。事实上，DRD 是由对疾病至关重要的基因突变引起的。 DA 合成，包括引起 DRD 的 TH 突变与一些残余 TH 活性相关，而消除 TH 活性的突变会导致儿童帕金森病，表明 TH 活性和 [DA] 是相关的。然而，引起肌张力障碍的 DA 信号功能障碍的性质尚不清楚，为了解决我们的知识空白，我们培育了一种携带人类 DRD 引起的 TH 中 Q381K 突变的敲入小鼠。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间恶化，以及对 L-DOPA 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 从基因到行为的机制。我们的初步数据表明，肌张力障碍是由 [DA] 介导的，[DA] <1。成人突触前 DA 的类似减少会导致帕金森病，因此，不同的突触后反应可能解释了帕金森病 (PD) 和 DA 传递减少的神经学后果的差异。事实上，我们的初步数据表明 D1R 超敏感、中型多棘神经元 (MSN) 过度兴奋、MSN 树突数量减少和皮质纹状体神经支配异常。因此，我们将检验生命早期 DA 缺乏与（不良）适应性相结合的假设。通过使用多学科方法来检查与肌张力障碍相关的 DA 传递减少的突触前和突触后后果，突触后反应会引起肌张力障碍。目的是： 1. 阐明单胺代谢与肌张力障碍严重程度之间的关系 2. 确定导致肌张力障碍的 DA 受体亚型和信号传导缺陷 3. 描述肌张力障碍的内在和突触特性的变化。 4. 检查 D1R 和 D2R 皮质纹状体突触的树突形态和超微结构变化。 DRD 小鼠中表达 D2R 的 MSN 对生命早期 DA 剥夺的反应。