Aberrant Synaptic Plasticity: Impact on Dopamine Graft Outcome

描述(申请人提供)：尽管左旋多巴有不可否认的好处，但帕金森病(PD)的对症治疗仍然不是最理想的。随着疾病的发展，治疗的益处可能会减少，而严重的副作用，如运动障碍，可能会施加额外的限制。此外，实验性的治疗方法，如将多巴胺(DA)神经元移植到帕金森病患者体内，产生了各种不同的、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提高生活质量至关重要。虽然人们的注意力集中在延缓黑质纹状体神经元的退化，通过改进的药理学来稳定纹状体DA，以及替换因疾病而失去的细胞的方法，但很少有人关注纹状体本身的病理状态如何影响DA的替代策略。在帕金森氏病死后脑中，纹状体中棘神经元(MSN)有明显的形态变化，包括晚期疾病患者树突棘的显著萎缩(McNeill等人，1988年；Zaja-Milatovic等人，2005年；Stephens等人，2005年)。据预测，这些变化将对治疗策略产生负面影响；然而，树突病理在帕金森病治疗中的作用尚未被调查。最近的一份报告(Day et al，2006)显示，就像在PD患者中看到的那样，大鼠或小鼠严重的DA耗竭导致MSN上的脊柱密度显著降低。此外，这些作者已经确定，纹状体MSN上的脊椎密度的丧失与脊髓内Cav1.3 L型钙通道的失调有关。这一机制的确定允许对本应用中提出的假设进行检验：1)MSN脊柱密度的退行性变化对DA替代疗法的疗效产生不利影响，包括左旋多巴和DA移植物；以及2)脊柱形态改变在左旋多巴诱导和/或移植物诱导的运动障碍行为的发展中起作用。拟议的研究将采用公认的帕金森症和运动障碍的大鼠模型。利用光镜和电子显微镜分析以及多种行为特征，我们将比较具有正常脊柱形态的DA耗竭大鼠和具有明显脊柱病理的DA耗竭大鼠的治疗益处和/或异常行为的发展。公共卫生相关性目前帕金森氏病的治疗方法并不理想。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。

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.