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（申请人证明）：肌张力障碍的特征是在尿中引起扭曲运动的非自愿性肌肉收缩。是一种原型障碍，用于理解异常的DA神经递质如何通过恢复L-DOPA或DA综合的DA信号后，造成了童年的发作，倾斜的羟化酶（通过DRD的突变）与某些残留性相关。为了在我们的知识中添加这个差距，我们在TH（DRD小鼠）中产生了Q381K突变的敲击小鼠。因此，l响应l，从而为我们提供了从基因到行为的前所未有的机会。对降低DA疾病（PD）和肌张力障碍的DA传播的差异的差异后反应的发散后反应。（MAL）突触后反应的生命DA差异通过使用方法来检查降低的DA与肌张力障碍的da降低后的肌张力障碍。肌张力障碍的每一个。响应于DRD小鼠的早期DA抑郁症，对早期寿命的DA抑制作用响应于D1R的D1R和D2R表达MSN的皮质突触变化。