Aberrant Synaptic Plasticity: Impact of Dopamine on Graft Outcome

异常的突触可塑性：多巴胺对移植结果的影响

• 批准号: 7625340
• 负责人: KATHY Steece STEECE-COLLIER
• 金额: $ 40.29万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-10-01 至 2009-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625340
• 关键词: Accounting; Adverse effects; Amphetamines; Animals; Antiparkinson Agents; Area; Atrophic; Award; Behavior; Behavioral; Brain; Brain region; Calcium Channel Blockers; Cell Count; Cell Survival; Cells; Chromosome Pairing; 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; Growth Factor; Hot Spot; Individual; Injection of therapeutic agent; Ipsilateral; Lesion; Levodopa; Light; Localized; Location; Mediating; Microscopic; Mink; Modeling; Monitor; Morphology; Mus; Neurons; Nimodipine; Numbers; Outcome; Output; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathology; Patients; Personal Satisfaction; Pharmacology; Pharmacotherapy; Physiological; Placement; Play; Rattus; Replacement Therapy; Reporting; Reserpine; Rodent; Role; Secondary to; Severities; Signal Transduction; Site; Source; Standards of Weights and Measures; Substantia nigra structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Thinking; Time; Tissue Grafts; Transgenic Mice; Translating; Treatment Efficacy; Vertebral column; Week; behavior test; cohort; day; density; dopamine graft; dopaminergic neuron; embryonic stem cell; experience; improved; indexing; median forebrain bundle; motor deficit; nerve supply; neurotrophic factor; prevent; reinnervation; research study; size; stem; success; therapy development; vector

Dopamine (DA) neuron grafts provides benefit in some individuals with Parkinson's disease (PD), however, overall efficacy is less than would be predicted from the degree of DA replacement provided in some. Further, an undesirable side-effect known as graft-induced dyskinesias develop in some patients. Many issues thought to underlie lack of graft success in PD are being investigated. Primary among these is low cell survival following grafting into the parkinsonian brain. However, we hypothesize that there are critical factors not yet considered that contribute to the overall lack of graft success. Specifically, the primary site for afferent input of nigral DA are medium spiny neurons (MSNs) within striatum. The numerous dendritic ¿spines¿ found on normal MSNs are critical sites of synaptic integration for nigral DA and cortical glutamate signaling. In advanced PD there is a marked atrophy of dendrites and spines on MSNs (McNeill, 1988; Zaja-Milatovic, 2005; Stephens, 2005). Additional alterations in spine morphology are thought to occur in the parkinsonian brain following long-term levodopa treatment (Sgambato-Faure, 2005; Picconi, 2005). The premise of this project is that these severe morphological alterations following severe DA depletion and/or long-term levodopa will have grave consequences for cell replacement therapies despite the number or type (e.g.: stem, embryonic) of cells grafted. Similar to PD, mice and rats with severe DA depletion also show significant decrease in spine density on MSNs. A new mechanism involving dysregulation of intraspine Cav1.3 Ca2+ channels has been found to account for this spine loss. Indeed, absence of Cav1.3 channels in transgenic mice or administration of the Cav1.3 antagonist nimodipine to parkinsonian rats can prevent spine loss in the presence of severe striatal DA depletion (Day, 2006). Identification of this mechanism allows testing the hypotheses put forth in this project: 1) degenerative changes in spine density of MSN has a detrimental impact on DA graft survival and efficacy; 2) altered spine morphology plays a role in the development of levodopa-induced and/or DA 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 to those with significant spine pathology.

多巴胺 (DA) 神经元移植物对某些帕金森病 (PD) 患者有益，但是， 总体疗效低于根据某些药物提供的 DA 替代程度预测的效果。 一些患者会出现一种不良副作用，即移植物引起的运动障碍。 正在研究PD移植失败的主要原因是细胞存活率低。 然而，在移植到帕金森病大脑后，我们再次认识到还存在一些关键因素。 认为导致移植失败的总体原因是传入输入的主要部位。 黑质 DA 是纹状体中的中型多刺神经元 (MSN)，有大量的树突 ¿刺??发现于 正常 MSN 是黑质 DA 和皮质谷氨酸信号传导突触整合的关键位点。 晚期 PD 的 MSN 上的树突和棘明显萎缩（McNeill，1988；Zaja-Milatovic，2005； Stephens，2005）。脊柱形态的其他改变被认为发生在帕金森病大脑中。 长期左旋多巴治疗后（Sgambato-Faure，2005；Picconi，2005） 该项目的前提是。 严重 DA 耗竭和/或长期左旋多巴后这些严重的形态学改变将产生 无论细胞的数量或类型（例如：干细胞、胚胎）如何，细胞替代疗法都会产生严重后果 与 PD 类似，DA 严重缺失的小鼠和大鼠的脊柱密度也显着降低。 已发现一种涉及脊柱内 Cav1.3 Ca2+ 通道失调的新机制。 事实上，转基因小鼠中缺乏Cav1.3通道或施用了Cav1.3通道。 Cav1.3拮抗剂尼莫地平对帕金森病大鼠可预防存在严重纹状体DA的脊柱损失 耗尽（Day，2006）。该机制的识别允许测试该项目中提出的假设：1） MSN 脊柱密度的退行性变化对 DA 移植物的存活和功效有疼痛影响 2) 脊柱形态的改变在左旋多巴诱导和/或 DA 移植物诱导的发展中发挥作用 拟议的研究将采用成熟的帕金森病大鼠模型和 使用光和电子显微镜分析和多种行为特征，我们将进行比较。 具有正常脊柱的 DA 耗尽大鼠的治疗益处和/或异常行为的发展 具有明显脊柱病理学特征的人的形态学。