Aberrant Synaptic Plasticity: Impact on Dopamine Graft Outcome

异常的突触可塑性：对多巴胺移植结果的影响

• 批准号: 7931899
• 负责人: KATHY Steece STEECE-COLLIER
• 金额: $ 26.69万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931899
• 关键词: Adverse effects; Amphetamines; Animals; Antiparkinson Agents; Area; Atrophic; Attention; Autopsy; Award; Behavior; Behavioral; Brain; Brain region; Calcium Channel Blockers; Cell Count; Cells; Chronic; Classification; Complex; Corpus striatum structure; Data; Dendritic Spines; Development; Disease; Dopamine; Dopamine Receptor; Dyskinetic syndrome; Electrons; Embryo; Environment; Etiology; Exhibits; GDNF gene; Glutamates; Gold; Golgi Apparatus; Graft Survival; Hot Spot; Immunohistochemistry; Injection of therapeutic agent; Ipsilateral; Label; Lesion; Levodopa; Light; Little' s Disease; Location; Mediating; Microscopic; Mink; Modeling; Monitor; Morphology; Mus; Neurons; Nimodipine; Outcome; Output; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathology; Pathway interactions; Patients; Pharmacology; Pharmacotherapy; Physiological; Play; Quality of life; Rattus; Replacement Therapy; Reporting; Reserpine; Rodent; Role; Secondary to; Severities; Site; Source; Specimen; Substantia nigra structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Grafts; Transgenic Mice; Translating; Treatment Efficacy; Vertebral column; advanced disease; behavior test; clinically significant; density; dopamine graft; dopaminergic neuron; experience; improved; indexing; median forebrain bundle; motor deficit; nerve supply; neurotrophic factor; novel therapeutics; prevent; public health relevance; reinnervation; research study; stem; therapy development

DESCRIPTION (provided by applicant): Despite the undeniable benefit of levodopa, symptomatic treatment for Parkinson's disease (PD) remains suboptimal. As the disease progresses, therapeutic benefit can wane, and significant side effects such as dyskinesias can impose additional limitations. Further, experimental therapeutic approaches such as grafting of replacement dopamine (DA) neurons into patients with PD have produced variable, and overall, disappointing results. Understanding factors that contribute to suboptimal therapeutics in this disease is critical to improving quality of life. While much attention has been focused on approaches to delay degeneration of nigrostriatal neurons, stabilize striatal DA by improved pharmacology, and replace cells lost to the disease, little attention has been given to how the pathological state of the striatum itself might impact DA replacement strategies. It is well documented in postmortem PD brains that there are distinct morphological alterations to striatal medium spiny neurons (MSNs) including significant atrophy of dendritic spines with advanced disease (McNeill et al, 1988; Zaja-Milatovic et al, 2005; Stephens et al, 2005). Such changes would be predicted to negatively impact therapeutic strategies; however, the role of dendritic pathology in PD therapeutics has not been investigated. A recent report (Day et al, 2006) has shown that, as seen in PD patients, severe DA depletion in rats or mice results in a dramatic reduction in spine density on MSNs. Further, these authors have determined that loss of spine density on striatal MSNs is related to dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Identification of this mechanism allows testing of the hypotheses put forth in this application: 1) degenerative changes in spine density of MSNs has a detrimental impact on the efficacy DA replacement therapies, including levodopa and DA grafts; and 2) altered spine morphology plays a role in the development of levodopa- induced and/or graft-induced dyskinetic behaviors. The proposed studies will employ the well-established rat model of parkinsonism & dyskinesia. Using light and electron microscopic analyses & multiple behavioral profiles, we will compare therapeutic benefit and/or development of abnormal behaviors between DA-depleted rats with normal spine morphology and those with significant spine pathology. PUBLIC HEALTH RELEVANCE Current therapeutics for Parkinson's disease is suboptimal. The proposed studies will explore issues not previously investigated that could have significant clinical significance for development of novel therapeutics for Parkinson's disease.

描述（由申请人提供）：尽管左旋多巴具有不可否认的益处，但帕金森病（PD）的对症治疗仍不理想。随着疾病的进展，治疗益处可能减弱，并且显著的副作用如运动障碍可能会带来额外的限制。此外，实验性治疗方法，如移植替代多巴胺（DA）神经元到PD患者产生了变量，和整体，令人失望的结果。了解导致这种疾病的次优治疗的因素对改善生活质量至关重要。虽然很多注意力都集中在方法来延迟黑质纹状体神经元的变性，稳定纹状体DA通过改进的药理学，并取代细胞损失的疾病，很少有人注意到纹状体本身的病理状态可能会影响DA的替代策略。在死后PD脑中有充分的证据表明，纹状体中棘神经元（MSN）存在明显的形态学改变，包括晚期疾病的树突棘显著萎缩（麦克尼尔等人，1988; Zaja-Milatovic等人，2005; Stephens等人，2005）。预计这种变化会对治疗策略产生负面影响;然而，尚未研究树突病理学在PD治疗中的作用。最近的一份报告（Day et al，2006）显示，如在PD患者中所见，大鼠或小鼠中严重的DA耗竭导致MSN上的棘密度显著降低。此外，这些作者已经确定纹状体MSN上的棘密度损失与棘内Cav1.3 L型Ca2+通道的失调有关。该机制的鉴定允许测试本申请中提出的假设：1）MSN的棘密度的退行性变化对DA替代疗法（包括左旋多巴和DA移植物）的功效具有不利影响;和2）改变的棘形态在左旋多巴诱导的和/或移植物诱导的运动障碍行为的发展中起作用。拟议的研究将采用完善的帕金森病和运动障碍大鼠模型。使用光学和电子显微镜分析和多种行为特征，我们将比较具有正常脊柱形态的DA耗尽大鼠和具有显著脊柱病理的DA耗尽大鼠之间的治疗益处和/或异常行为的发展。公共卫生相关性目前帕金森病的治疗方法是次优的。拟议的研究将探索以前没有研究过的问题，这些问题可能对开发帕金森病的新疗法具有重要的临床意义。