Targeting the NMDA receptor-mediated disruption of autonomous subthalamic nucleus activity to ameliorate physiological and motor symptoms in a mouse model of Parkinson's Disease

靶向 NMDA 受体介导的丘脑自主核活动破坏，改善帕金森病小鼠模型的生理和运动症状

• 批准号: 8981733
• 负责人: Eileen McIver
• 金额: $ 4.36万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8981733
• 关键词: Address; Animals; Basal Ganglia; Behavioral; Behavioral Assay; Brain; Cell physiology; Cells; Chronic; Communication; Data; Deep Brain Stimulation; Disease; Disease model; Dopamine; Electrophysiology (science); Experimental Parkinsonism; Frequencies; Functional disorder; Future; Goals; Health; Human; Hydrogen Peroxide; Hydroxydopamines; Idiopathic Parkinson Disease; Knock-out; Knowledge; Lead; Lesion; Link; Mediating; Mission; Modeling; Molecular; Motor; Movement; Mus; N-Methyl-D-Aspartate Receptors; National Institute of Neurological Disorders and Stroke; Neurons; Nitric Oxide; Oxidative Stress; Parkinson Disease; Pathway interactions; Patients; Pattern; Pharmacogenetics; Physiological; Potassium; Production; Research; Role; Signal Pathway; Signal Transduction; Structure of subthalamic nucleus; Substantia nigra structure; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Training; Transgenic Organisms; Up-Regulation; Viral Vector; behavior test; designer receptors exclusively activated by designer drugs; dopaminergic neuron; genetic manipulation; in vivo; knock-down; motor disorder; motor symptom; mouse model; nervous system disorder; novel therapeutic intervention; prevent; research study; restoration; skills

DESCRIPTION (provided by applicant): The degeneration of substantia nigra dopamine neurons drives the core motor symptoms of idiopathic and experimental Parkinson's disease (PD) by profoundly altering the frequency and pattern of activity in the cortico-basal ganglia-thalamo-cortical loop. The classical rate model of basal ganglia dysfunction suggests that loss of dopamine results in an increase in the activity of the indirect (movement-inhibiting) pathway relative to the activity of the direct (movement-promoting) pathway. However, therapeutic interventions such as L-DOPA and deep brain stimulation (DBS) of the subthalamic nucleus (STN) do not alter firing rates in a manner that is consistent with the rate model. Instead, the amelioration of motor symptoms in experimental and idiopathic PD is more closely related to reductions in abnormal, persistent, synchronous, band (13-30Hz) activity. However, the causes of abnormal-band activity in PD remain poorly defined. We have found that the autonomous activity of the STN, which is a component of the indirect and hyperdirect pathways, is lost in the unilateral 6-hydroxydopamine (6- OHDA) lesion model of PD. Loss of activity appears to be through NMDA receptor (R)-mediated upregulation of an ATP-dependent potassium (KATP) channel conductance that hyperpolarizes STN neurons. Loss of decorrelating autonomous STN activity may increase cortical patterning of the STN and thus contribute to the amplification and persistence of band activity in PD and its models. The proposed project will therefore investigate the mechanisms underlying the disruption of autonomous STN activity and determine whether the rescue of intrinsic STN excitability is therapeutic in experimental PD. Using a combination of viral vector-mediated genetic manipulations, electrophysiological recording ex vivo and in vivo and motor behavioral testing in the 6-OHDA mouse model of PD, 3 Specific Aims will be addressed. The applicant will determine: 1) whether knockdown of STN NMDA receptors in vivo prevents loss of autonomous STN activity, and the NMDAR-linked signaling pathways that upregulate STN KATP channels; 2) whether knockdown of STN NMDARs normalizes cortico-basal ganglia-thalamo- cortical loop activity and ameliorates motor dysfunction; and 3) whether restoration of intrinsic STN activity through expression and activation of designer receptors exclusively activated by designer drugs (DREADDs) normalizes cortico-basal ganglia-thalamo-cortical loop activity and ameliorates motor dysfunction. Through the proposed training plan the applicant will gain expertise in molecular, electrophysiological, anatomical and behavioral techniques and develop the analytical and communication skills necessary to achieve her goal of becoming an independent neuroscientist focused on disease mechanisms and therapeutics.

描述（由申请人提供）：尼格拉多巴胺神经元的变性通过深刻改变皮质 - 基因神经节神经神经神经节 - thalamo - thalamo-cortical loop的活性频率和模式，驱动特发性和实验帕金森氏病（PD）的核心运动症状。基底神经节功能障碍的经典速率模型表明，相对于直接（运动促进）途径的活性，多巴胺的丧失导致间接（抑制运动）途径的活性增加。然而，丘脑核（STN）的L-DOPA和深脑刺激（DB）等治疗性干预措施不会以与速率模型一致的方式改变发射速率。取而代之的是，实验性和特发性PD中运动症状的改善与降低异常，持续性，同步，频带（13-30Hz）活性的减少密切相关。但是，PD中带异常活性的原因仍然很差。我们发现，在单方面的6-羟基多巴胺（6- OHDA）病变模型中，STN的自主活动是间接和高直接途径的组成部分。活性丧失似乎是通过NMDA受体（R）介导的ATP依赖性钾（KATP）通道电导的上调，该通道电导使STN神经元超极化。解相关的自主STN活性的丧失可能会增加STN的皮质模式，从而有助于PD及其模型中带活性的扩增和持久性。因此，拟议的项目将研究自主STN活性破坏的基础机制，并确定在实验性PD中挽救内在的STN兴奋性是否具有治疗性。使用病毒载体介导的遗传操作，电生理记录离体和体内和运动行为测试在PD的6-OHDA小鼠模型中，将解决3个具体目标。申请人将确定：1）在体内敲低STN NMDA受体是否可以防止自主性STN活性的损失，以及上调stn Katp通道的NMDAR连接信号通路； 2）STN NMDARS的敲低是否使皮质 - 基质神经节 - thalamo-Cortical Loop活性正常化并改善运动功能障碍； 3）是否通过表达和激活设计器受体的表达和激活固有的STN活性恢复了由设计器药物（Dreadds）激活（Dreadds）将皮质 - 基质神经节神经节 - 塔拉莫 - 皮质环的活性归一化，并减轻运动功能障碍。通过拟议的培训计划，申请人将获得分子，电生理，解剖学和行为技术的专业知识，并发展出她成为专注于疾病机制和疗法的独立神经科学家所必需的分析和沟通技巧。