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：
9203641
负责人：
ELLEN J. HESS
金额：
$ 35.2万
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/9203641
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（由适用提供）：肌张力障碍的特征是非自愿肌肉收缩会导致扭曲运动和姿势。在许多不同形式的肌张力障碍中始终观察到多巴胺（DA）神经传递的异常，但是引起肌张力障碍的DA缺陷知之甚少。 L-DOPA反应性肌张力障碍（DRD）被认为是一种原型障碍，用于了解异常DA神经传递如何引起肌张力障碍。 DRD的特征是童年发作肌肌张力障碍，并具有昼夜波动，整个一天中的症状都令人惊讶。 DRD的区别是用L-DOPA或DA激动剂恢复DA信号后症状的显着改善。实际上，DRD是由对DA合成至关重要的基因的突变引起的，包括酪氨酸羟化酶（Th）。 DRD引起的TH突变与某些残留活性有关，而废除TH活性的突变会导致儿童帕金森氏症表明TH活性和[DA]是肌张力障碍发展的关键决定者。但是，引起肌张力障碍的DA信号传导功能障碍的性质尚不清楚。为了解决这一差距，我们产生了一种敲击小鼠，该小鼠带有人类DRD引起的Q381K突变（DRD小鼠）。像人类疾病一样，DRD小鼠表现出降低的活性，[DA]的降低，整个活性期间的肌张力障碍运动恶化以及响应L-DOPA的肌张力障碍的改善。这是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，可以剖析DRD从基因到行为的DRD的机制。我们的初步数据表明，肌张力障碍是由[DA]介导的，占正常的1％。成年人的突触前DA的类似减少会导致帕金森氏症。因此，发散的突触后反应可能解释了帕金森氏病（PD）和肌张力障碍之间DA传播的神经系统差异的差异。实际上，我们的初步数据表明D1R超敏反应，中刺神经元（MSN）过度刺激性，MSN树突数量的减少和皮质皮质神经神经神经神经神经差的异常。因此，我们将检验以下假设：早期生命DA缺乏与（MAL）适应性突触后反应结合使用，通过使用多学科方法来检查与肌张力障碍相关的DA传播的降低DA传播的前和突触后后果，从而引起肌张力障碍。具体目的是：1。阐明单胺代谢与肌张力障碍的严重程度之间的关系。 2。确定导致肌张力障碍的DA受体亚型和信号缺陷。 3。描述D1和D2R表达MSN的固有和突触特性的改变。 4。检查皮质纹状体突触的树突形态和超微结构变化，以响应于DRD小鼠的早期寿命DA剥夺，表达D2R的MSN。