Aberrant Synaptic Plasticity: Impact of Dopamine on Graft Outcome

多巴胺（DA）神经元移植物在一些患有帕金森病（PD）的个体中提供了益处，然而， 总体疗效低于根据某些研究中提供的DA替代程度所预测的疗效。此外，本发明还 在一些患者中产生了不希望的副作用，称为移植物诱导的运动障碍。许多问题认为 导致腹膜透析移植失败的原因正在研究中。其中最主要的是细胞存活率低 移植到帕金森病患者的大脑后然而，我们假设有一些关键因素还没有 这被认为是导致移植成功率整体不足的原因。具体来说，传入输入的主要部位 黑质DA是纹状体内的中型多刺神经元（MSN）。发现的大量树突状棘 正常MSN是黑质DA和皮质谷氨酸信号传导的突触整合的关键位点。在 在晚期PD中，MSN上的树突和棘显著萎缩（麦克尼尔，1988; Zaja-Milatovic，2005; Stephens，2005）。脊椎形态的其他改变被认为发生在帕金森病患者的大脑中 长期左旋多巴治疗后（Sgambato-Faure，2005; Picconi，2005）。这个项目的前提是 这些严重的形态学改变后，严重的DA耗竭和/或长期左旋多巴将有 细胞替代疗法的严重后果，无论数量或类型（例如：干，胚胎）细胞 嫁接的与PD相似，严重DA耗竭的小鼠和大鼠也显示出显著的脊柱密度降低 在MSN上。已经发现了一种涉及脊髓内Cav1.3 Ca 2+通道失调的新机制， 造成了脊椎的缺失事实上，在转基因小鼠中Cav1.3通道的缺乏或施用 Cav1.3拮抗剂尼莫地平对帕金森病大鼠纹状体DA严重时脊髓损伤的预防作用 消耗（Day，2006）。识别这种机制可以测试本项目中提出的假设：1） MSN棘密度的退行性变化对DA移植物的存活和有效性具有不利影响; 2） 改变的脊柱形态在左旋多巴诱导的和/或DA移植诱导的 运动障碍行为拟议中的研究将采用完善的帕金森症大鼠模型& 运动障碍使用光镜和电镜分析及多种行为特征，我们将比较 DA耗竭大鼠与正常脊柱之间的治疗获益和/或异常行为的发生 与那些有明显脊柱病理学的人相比。

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.