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氏病（PD）的基础。 DA末端突触到纹状体培养基神经元（MSN）上，形成与皮质纹状体谷氨酸能突触的三合会；兴奋性皮质输入通常位于树突状脊柱的头部，然后将DA突触到脊柱颈部。因此，DA将其定位为MSN的门兴奋性谷氨酸能输入。通过纹状体DA的水平降低，并试图在渐进性DA损失时保持正常功能，将多种补偿机制设置为发挥作用。某些变化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）病变导致树突状脊柱密度降低，MSN的树突长度降低； PD中已经报道了类似的情况。已显示谷氨酸分别通过NMDA和AMPA受体调节脊柱形成和维持。我们假设纹状体DA耗竭可通过增加谷氨酸能传播而导致树突脊柱密度降低，从而导致细胞内钙水平的增加。 [Ca2+] I的增加导致脊柱缩短和损失，从而将兴奋性驱动到MSN。但是，这些树突状 变化还可以通过丧失树突受体居住的树突状刺来限制DA替代处理的有效性。这种程序化的工作将通过四个项目来检验这一假设。 第一个项目将确定在D2受体处的DA音调损失是否导致MSN的树突变化，并检验以下假设：通过L型钙通道钙涌入是一种效应子。第二个项目研究了MSN中CAMKII的多巴胺能调节；这种树枝状转录的Ca2+依赖性酶调节了NMDA受体的AMPA受体和2B亚基的磷酸化，因此是激发谷氨酸乳突性传播的有效性的关键。第三个项目检验了钙调神经酶（PP2B）是通过D2受体募集的Ca2+激活的磷酸酶，它可以调节谷氨酸能驱动到MSNS，并确定MSN中MSN中脊柱密度的降低是否通过遗传上或下降的PP2B下降而改变。最终项目将确定PD患者的验尸材料中的光和电子显微镜水平的树突形态的变化，并将树突状的变化与临床状况相关。这项工作还将确定脊柱损失伴随的突触重组形式。这些项目应阐明 PD并可能导致旨在减慢或停止疾病进展的新策略。