Aberrant Synaptic Plasticity: Impact on Dopamine Graft Outcome

描述（由申请人提供）：尽管左旋多巴具有不可否认的益处，但对帕金森病（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，而运动障碍等显著的副作用可能会施加额外的限制。此外，将替代多巴胺（DA）神经元移植到PD患者体内的实验性治疗方法产生了不同的、总体上令人失望的结果。了解导致治疗方法不理想的因素对提高生活质量至关重要。虽然很多人关注延缓黑质纹状体神经元退化的方法，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，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。有充分的证据表明，死后PD患者的大脑纹状体中棘神经元（MSNs）存在明显的形态学改变，包括随着疾病进展，树突棘明显萎缩（McNeill等人，1988；Zaja-Milatovic等人，2005；Stephens等人，2005）。预计这些变化会对治疗策略产生负面影响；然而，树突病理在PD治疗中的作用尚未被研究。最近的一份报告（Day et al, 2006）表明，在PD患者中，大鼠或小鼠严重的DA耗损会导致msn上脊柱密度的急剧降低。此外，这些作者已经确定纹状体msn上的脊柱密度损失与脊柱内Cav1.3 l型Ca2+通道的失调有关。确定这一机制可以验证本应用中提出的假设：1)msn脊柱密度的退行性变化对左旋多巴和DA移植等DA替代疗法的疗效有不利影响；2)脊柱形态的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。拟建的研究将采用成熟的帕金森病和运动障碍大鼠模型。通过光镜和电镜分析以及多种行为特征，我们将比较正常脊柱形态的da耗尽大鼠和脊柱病理明显的大鼠的治疗效果和/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尚不理想。拟议的研究将探索以前未研究的问题，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.