"Profiles of Maladaptive Plasticity: Impact on Graft and Levodopa Efficacy"

直觉）： 多巴胺（DA）神经元的移植在一些患有帕金森病（PD）的个体中提供益处，然而， 总体疗效低于从许多个体中提供的DA替代程度所预测的。 类似地，虽然帕金森病大鼠的DA移植物可以完全逆转安非他明诱导的旋转，但更多的是， 复杂的运动行为通常表现出很少或没有改善。许多问题被认为是缺乏贪污的基础 PD的成功正在研究中。其中最主要的是移植到老年人体内后细胞存活率低， 帕金森病患者的大脑然而，我们假设，有一些关键因素尚未考虑，有助于 移植成功率的整体缺乏。具体来说，黑质DA和皮质DA传入输入的主要部位 谷氨酸神经元是纹状体内的中型多刺神经元（MSN）。无数的树枝状“棘” 在正常MSN上发现的是DA和谷氨酸信号传导的突触整合的关键位点。晚期PD MSN上的树突和棘显著萎缩（麦克尼尔，1988; Zaja-Milatovic，2005; Stephens， 2005年）。这个项目的前提是，这些严重的形态变化将产生严重的后果， 细胞替代疗法，尽管移植的细胞数量。神经元结构的病理改变 也预期会对传统的多巴胺替代药物疗法产生负面影响。与PD相似，小鼠 重度DA耗竭的大鼠MSNs上的棘密度也显著降低。重要的是，新 已经发现涉及脊柱内Cav1.3Ca2+通道失调的机制解释了这种脊柱 损失事实上，在转基因小鼠中不存在Cavl. 3通道或施用Cavl. 尼莫地平对6-OHDA损伤的大鼠可以在存在严重的纹状体DA耗竭的情况下防止脊柱丢失（Day， 2006年）。这种机制的识别允许测试本项目中提出的假设：1）退化性 MSN棘密度的变化对DA移植物的有效性有不利影响; 2）改变棘形态 在左旋多巴诱导的和/或DA移植物诱导的运动障碍行为的发展中起作用。的 所提议的研究将使用已建立的帕金森综合征和运动障碍的大鼠模型。使用光和 电子显微镜分析和多种行为特征，我们将比较治疗益处和/或 具有正常脊柱形态的DA耗尽大鼠与具有正常脊柱形态的DA耗尽大鼠之间的异常行为的发展。 严重脊柱萎缩我们将进一步调查高龄的风险因素如何影响潜力 树突棘再生 相关性（见说明）： 项目1将提供新的见解纹状体病理的作用，特别是损失树突棘上， 中等多刺输出神经元多巴胺替代疗法这些研究可以改善 帕金森病患者的治疗效果。

Instmctions): Grafting of dopamine (DA) neurons 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 many individuals. Similarly, while DA grafts in parkinsonian rats can completely reverse amphetamine-induced rotations, more complex motor behaviors often show little to no improvement. 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 aged, 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 and cortical glutamate neurons are medium spiny neurons (MSNs) within striatum. The numerous dendritic "spines" found on normal MSNs are critical sites of synaptic integration for DA and glutamate signaling. In advanced PD there is a marked atrophy of dendrites and spines on MSNs (McNeill, 1988; Zaja-Milatovic, 2005; Stephens, 2005). The premise of this project is that these severe morphological alterations will have grave consequences for cell replacement therapies despite the number of cells grafted. Pathological alterations of neuron structure would also be expected to negatively impact traditional dopamine replacement pharmacotherapies. Similar to PD, mice and rats with severe DA depletion also show significant decrease in spine density on MSNs. Importantly, a new mechanism involving dysregulation of intraspine Cavl.3 Ca2+ channels has been found to account for this spine loss. Indeed, absence of Cavl.3 channels in transgenic mice or administration of the Cavl.3 antagonist nimodipine to 6-OHDA lesioned 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 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 and dyskinesia. Using light and electron microscopic analyses and 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 atrophy. We will further investigate how the risk factor of advanced age may impact potential dendritic spine regeneration. RELEVANCE (See Instructions): Project 1 will provide novel insight into the role of striatal pathology, specifically loss of dendritic spines on medium spiny output neurons, on dopamine replacement therapy. These studies may allow for improved treatment efficacy for patients with Parkinson's disease.