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）：黑质多巴胺神经元的变性通过深刻改变皮质-基底节-丘脑-皮质环的活动频率和模式，驱动特发性和实验性帕金森病（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，多巴胺的损失导致间接（运动抑制）途径的活性相对于直接（运动促进）途径的活性增加。然而，治疗干预，如左旋多巴和脑深部电刺激（DBS）的丘脑底核（DBS）不改变放电率的方式是一致的速率模型。相反，实验性和特发性PD中运动症状的改善与异常、持续、同步、频带（13- 30 Hz）活动的减少更密切相关。然而，PD异常带活动的原因仍然不清楚。我们已经发现，自主活动，这是一个组成部分的间接和超直接的途径，失去了在单侧6-羟基多巴胺（6- OHDA）病变模型的PD。活动的丧失似乎是通过NMDA受体（R）介导的ATP依赖性钾（KATP）通道电导的上调，使海马神经元超极化。失去相关的自主神经元活动可能会增加皮层图案的神经元，从而有助于放大和持久性的带活动在PD及其模型。因此，拟议的项目将调查的机制，自主神经元活动的中断，并确定是否拯救内在的神经元兴奋性是治疗实验性PD。在6-OHDA PD小鼠模型中，使用病毒载体介导的遗传操作、离体和体内电生理记录以及运动行为测试的组合，将解决3个特定目的。申请人将确定：1）体内敲除STN NMDA受体是否可以防止自主性STN活性的丧失，以及上调STN KATP通道的NMDAR相关信号通路的丧失; 2）敲除STN NMDAR是否可以使皮质-基底节-丘脑-皮质环路活动正常化并改善运动功能障碍;和3）是否通过表达和激活专门由设计药物激活的设计受体来恢复固有的抗肿瘤活性（DREADDs）使皮质-基底节-丘脑-皮质环活动正常化并改善运动功能障碍。通过拟议的培训计划，申请人将获得分子，电生理，解剖和行为技术方面的专业知识，并发展必要的分析和沟通技能，以实现她成为专注于疾病机制和治疗的独立神经科学家的目标。