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

实例)： 移植多巴胺(DA)神经元对一些帕金森氏病(PD)患者有好处，然而， 总体疗效低于从许多个体提供的DA替代程度预测的效果。 同样，虽然帕金森病大鼠的DA移植可以完全逆转苯丙胺诱导的旋转，但更多 复杂的运动行为通常几乎没有改善。许多问题被认为是缺乏腐败的根本原因 帕金森病的成功正在调查中。其中最主要的是移植到老年人体内后细胞存活率低， 帕金森氏症患者的大脑。然而，我们假设，有一些关键因素尚未考虑到，这些因素有助于 总体上缺乏成功的贪污行为。具体地说，黑质DA和大脑皮层传入的主要部位 谷氨酸神经元是纹状体内的中棘神经元。无数的树枝状“刺” 在正常的MSN上发现的是DA和谷氨酸信号的突触整合的关键部位。在晚期帕金森病 MSN上有明显的树突和棘突萎缩(McNeill，1988；Zaja-Milatovic，2005；Stephens， 2005)。这个项目的前提是，这些严重的形态变化将对 尽管移植的细胞数量很多，但细胞替代疗法。神经元结构的病理改变会 预计还将对传统的多巴胺替代药物疗法产生负面影响。与帕金森病相似的小鼠 严重DA耗竭的大鼠在MSN上的脊椎密度也显著降低。重要的是，一个新的 已发现与脊髓内腔钙通道失调有关的机制可解释这一脊柱 损失。事实上，在转基因小鼠中缺乏Cavl.3通道或给予Cavl.3拮抗剂 尼莫地平给6-羟色胺损毁的大鼠可以在纹状体DA严重耗竭的情况下防止脊柱丢失(Day， 2006)。对这一机制的识别可以检验本项目中提出的假设：1)退化 MSN脊柱密度的变化对DA移植物的疗效有不利影响；2)脊柱形态改变 在左旋多巴诱导和/或DA移植物诱导的运动障碍行为的发展中起作用。这个 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。使用灯光和 电子显微镜分析和多种行为特征，我们将比较治疗效果和/或 脊椎形态正常的DA耗竭大鼠到脊椎发育不良大鼠的异常行为发展 严重的脊椎萎缩。我们将进一步调查高龄风险因素如何影响潜力。 树突棘再生。 相关性(请参阅说明)： 项目1将为纹状体病理的作用提供新的见解，特别是树突棘的丢失。 中等多刺输出神经元，多巴胺替代疗法。这些研究可能允许改进 帕金森氏病患者的治疗效果。

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.