Dendritic Plasticity in Parkinson's Disease

帕金森病的树突可塑性

• 批准号: 6766759
• 负责人: ARIEL Y DEUTCH
• 金额: $ 100.59万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766759
• 关键词: Parkinson' s disease; cellular pathology; clinical research; dendrites; dopamine; neural plasticity

DESCRIPTION (provided by applicant): A decrease in striatal dopamine (DA) concentration underlies Parkinson's disease (PD). DA terminals synapse onto striatal medium spiny neurons (MSNs), forming a triad with corticostriatal glutamatergic synapses; the excitatory cortical input is typically onto the head of the dendritic spine and the DA synapse onto the spine neck. DA is thereby critically positioned to gate excitatory glutamatergic inputs to MSNs. A variety of compensatory mechanisms are set into play by decreased striatal DA levels and attempt to maintain normal function in the face of progressive DA loss. Certain changes may afford some benefit but may ultimately be counterproductive. 6-hydroxydopamine (6-OHDA) lesions of the striatal DA innervation result in decreased dendritic spine density and decreased dendritic length in MSNs; a similar picture has been reported in PD. Glutamate has been shown to regulate spine formation and maintenance through NMDA and AMPA receptors, respectively. We hypothesize that striatal DA depletion results in decreased dendritics spine density by increasing glutamatergic transmission, which causes an increase in intracellular calcium levels. The increase in [Ca2+]i results in spine shortening and loss, thus delimiting excitatory drive onto the MSN. However, these dendritic changes may also limit the effectiveness of DA replacement treatment through loss of dendritic spines, on which DA receptors reside. This programmatic effort will test this hypothesis through four projects. The first project will determine if loss of DA tone at the D2 receptor is responsible for the dendritic changes in MSNs, and test the hypothesis that calcium influx through L-type calcium channels is an effector. The second project examines the dopaminergic regulation of CaMKII in the MSN; this dendritically-transcribed Ca2+-dependant enzyme regulates phosphorylation of the GluRl subunit of the AMPA receptor and 2B subunit of the NMDA receptor, and is thus a key to effectiveness of excitatoty glutamatergic transmission. The third project tests the hypothesis that calcineurin (PP2b), a Ca2+- activated phosphatase recruited by dopamine signaling through the D2 receptor, regulates glutamatergic drive onto MSNs and will determine if the decrease in spine density in MSNs is altered by genetic up- or down-regulation of PP2b. The final project will determine changes in dendritic morphology at both the light and electron microscopic level in postmortem material from PD patients and correlate dendritic changes with clinical status; this work will also determine the forms of synaptic reorganization that accompany spine loss. These projects should shed light on the pathophysiology of PD and may lead to development of new strategies aimed at slowing or halting disease progression.

描述（由申请人提供）： 纹状体多巴胺 (DA) 浓度的降低是帕金森病 (PD) 的基础。 DA 末端突触连接至纹状体中型多棘神经元 (MSN)，与皮质纹状体谷氨酸能突触形成三联体；兴奋性皮层输入通常位于树突棘的头部，而 DA 突触则位于脊柱颈部。因此，DA 的关键位置是控制 MSN 的兴奋性谷氨酸能输入。纹状体 DA 水平降低会启动多种补偿机制，并在 DA 逐渐丧失的情况下尝试维持正常功能。某些改变可能会带来一些好处，但最终可能会适得其反。纹状体 DA 神经支配的 6-羟基多巴胺 (6-OHDA) 损伤导致 MSN 中树突棘密度降低和树突长度缩短； PD 中也报道过类似的图片。谷氨酸已被证明可以分别通过 NMDA 和 AMPA 受体调节脊柱的形成和维护。我们假设纹状体 DA 消耗通过增加谷氨酸传输而导致树突棘密度降低，从而导致细胞内钙水平增加。 [Ca2+]i 的增加导致脊柱缩短和损失，从而限制了 MSN 的兴奋性驱动。然而，这些树突 变化还可能通过 DA 受体所在的树突棘的损失来限制 DA 替代治疗的有效性。这项计划工作将通过四个项目来检验这一假设。 第一个项目将确定 D2 受体处 DA 张力的丧失是否是 MSN 树突状变化的原因，并测试通过 L 型钙通道的钙流入是效应器的假设。第二个项目检查 MSN 中 CaMKII 的多巴胺能调节；这种树突转录的Ca 2+ 依赖性酶调节AMPA受体的GluR1亚基和NMDA受体的2B亚基的磷酸化，因此是兴奋性谷氨酸能传递有效性的关键。第三个项目测试了以下假设：钙调神经磷酸酶 (PP2b) 是一种由多巴胺信号通过 D2 受体募集的 Ca2+ 激活磷酸酶，调节 MSN 上的谷氨酸能驱动，并将确定 MSN 中脊柱密度的降低是否因遗传上调或下调而改变。 -PP2b的调节。最终项目将在光和电子显微镜水平上确定 PD 患者尸检材料中树突形态的变化，并将树突变化与临床状态相关联；这项工作还将确定伴随脊柱损失的突触重组的形式。这些项目应该阐明以下疾病的病理生理学： PD 可能会导致旨在减缓或阻止疾病进展的新策略的开发。