Effects of TNFalpha on Excitatory Synaptic Transmission

TNFα 对兴奋性突触传递的影响

• 批准号: 6744302
• 负责人: DAVID D STELLWAGEN
• 金额: $ 5.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744302
• 关键词: AMPA receptors; NMDA receptors; astrocytes; biological signal transduction; cell cell interaction; electrical measurement; electrophysiology; hippocampus; inhibitor /antagonist; long term potentiation; neural plasticity; neural transmission; neurophysiology; neuroregulation; neurotransmitter transport; receptor expression; synapses; tissue /cell culture; tumor necrosis factor alpha; voltage /patch clamp

DESCRIPTION (provided by applicant): The regulation of the AMPA subtype of the glutamate receptor is believed to contribute to long term changes in synaptic strength; changes believed to be important for many forms of experience-dependent plasticity. The surface expression of AMPA receptors (AMPARs) appears to be tightly regulated despite their constant cycling. In addition AMPAR surface expression has been shown to rapidly increase or decrease in response to stimulation. The detailed molecular mechanisms underlying AMPAR receptor trafficking, however, remain elusive. In this proposal, I outline a series of experiments that will investigate how the inflammatory cytokine tumor necrosis factor-alpha (TNFalpha), which has been shown to alter excitatory synaptic transmission, impacts AMPAR trafficking. Preliminary data suggests that TNFalpha induces a robust and rapid increase in the surface expression of AMPARs in cultured neurons. I will confirm this observation and examine if this increase is occurring at synaptic sites. I will then test whether TNFalpha has an endogenous role in maintaining AMPAR surface expression and begin to determine the molecular signaling pathways involved. These data should significantly enhance our knowledge of AMPAR trafficking and the influence of TNFalpha on synaptic function.

描述（由申请人提供）：对AMPA亚型的法规 谷氨酸受体被认为会导致突触的长期变化 力量;被认为对多种形式很重要的变化 依赖经验的可塑性。 AMPA受体的表面表达 （AMPAR）尽管持续骑自行车，但仍受到严格的调节。在 已显示添加AMPAR表面表达迅速增加或 减少刺激。详细的分子机制 但是，基本的AMPAR受体贩运仍然难以捉摸。在这个 提案，我概述了一系列实验，这些实验将研究如何 炎性细胞因子肿瘤坏死因子-Alpha（TNFalpha）， 显示以改变兴奋性突触传播，影响AMPAR运输。 初步数据表明，TNFalpha诱导了强劲而快速的增加 培养神经元中AMPAR的表面表达。我将确认 观察并检查这种增加是否在突触部位发生。我会 然后测试tnfalpha在维持AMPAR表面中是否具有内源作用 表达并开始确定所涉及的分子信号通路。 这些数据应大大增强我们对AMPAR贩运和 TNFALPHA对突触功能的影响。