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）的对症治疗仍然不够理想。随着疾病的进展，治疗效果可能会减弱，并且运动障碍等显着副作用可能会带来额外的限制。此外，实验性治疗方法，例如将替代多巴胺 (DA) 神经元移植到 PD 患者体内，已经产生了不同的、总体上令人失望的结果。了解导致这种疾病治疗效果不佳的因素对于提高生活质量至关重要。虽然很多注意力都集中在延缓黑质纹状体神经元退化、通过改进药理学稳定纹状体 DA 以及替换因疾病而丢失的细胞的方法上，但很少有人关注纹状体本身的病理状态如何影响 DA 替代策略。在死后 PD 大脑中，有充分证据表明，纹状体中型多棘神经元 (MSN) 存在明显的形态学改变，包括晚期疾病时树突棘的显着萎缩（McNeill 等，1988；Zaja-Milatovic 等，2005；Stephens 等， 2005）。预计此类变化会对治疗策略产生负面影响；然而，树突状病理学在帕金森病治疗中的作用尚未得到研究。最近的一份报告（Day 等，2006）表明，正如在 PD 患者中所见，大鼠或小鼠的严重 DA 消耗导致 MSN 上的脊柱密度急剧减少。此外，这些作者还确定纹状体 MSN 上棘密度的丧失与棘内 Cav1.3 L 型 Ca2+ 通道的失调有关。该机制的识别允许测试本申请中提出的假设：1) MSNs 脊柱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）的功效产生不利影响； 2)改变的脊柱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发挥作用。拟议的研究将采用成熟的帕金森症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和具有显着脊柱病理学的 DA 耗尽大鼠之间的治疗效果和/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并不理想。拟议的研究将探索以前未研究过的问题，这些问题可能对帕金森病新疗法的开发具有重要的临床意义。