NMDA Receptor Dynamics After Brain Injury

在工业化世界中，脑损伤是年轻人致残率和发病率的主要原因。 使用谷氨酸NMDA受体(NMDAR)拮抗剂治疗意外脑损伤的尝试已经 在几个主要的临床试验中都没有产生任何结果的改善。这些试验是基于 假设颅脑损伤后的神经功能障碍至少部分是 NMDAR过度激活与“兴奋性毒性”。 这项拟议研究背后的工作假设有三个方面： 1.脑损伤后NMDAR的过度激活是短暂的，并让位于长期的功能减退； 2.脑损伤后的认知障碍是由于脑组织中的 NMDA受体。 3.延迟激活NMDAR可能加速脑损伤后功能的恢复。 第二种假说认为，大脑的某些区域，如海马体，与生俱来 比其他人更容易受到脑损伤。我们建议在关闭的小鼠身上测试这些假设 头部损伤；钝性头部创伤的动物模型。NMDAR可用性的地区性变化和 功能(激活)状态将在受伤后5分钟至60天的时间内使用 使用依赖的配体MK801的定量放射自显影。NMDAR的生理相关性研究 将使用电生理学(长时程增强)来测量HYEPR激活和低激活。 认知缺陷将在损伤后14天和60天使用两种不同的任务进行测试；对象 在给予完全激动剂NMDA的动物中进行识别测试和Morris水迷宫， 部分NMDAR激动剂d-环丝氨酸或拮抗剂MK801在不同时间点和频率 在受伤之后。最后，几种可能的机制对NMDAR动态变化的贡献 脑损伤后将通过1.剂量反应和动力学研究之间的关系 NMDAR激活和功能反应的剂量和持续时间2.实验条件的调整 NMDAR必需的NR1单位和NR2亚单位的免疫组织化学染色。 这项拟议的研究聚焦于NMDAR的命运，NMDAR是一种被认为在 脑损伤的病理学。脑损伤是一个主要的公共卫生问题，因为它与死亡有关 长期残疾的受害者占相当大的比例，他们大多是年轻人。结果是 可能解释NMDAR拮抗剂在临床试验中失败的原因，并提出新的治疗策略 脑损伤的症状。

Brain injury is a leading cause of moratlity and morbidity among young people in the industrialized world. Attempts to treat accidental brain injuries with glutamate NMDA receptor (NMDAR) antagonists have failed to.produce any improvement in outcome in several major clinical trials. These trials were predicated on the hypothesis that neurological deficits after head injury are, at least in part, the result of hyperactivation of NMDAR and "excitotoxicity". The working hypothesis behind the proposed studies is three fold: 1. Hyperactivation of NMDAR after head injury is short lived and gives way to prolonged hypofunction; 2. The cognitive deficits after brain injury are a results of underactivation, rather than overactivation, of NMDA receptors. 3. Delayed activation of NMDAR may accelerate recovery of function after brain injury. A secondary hypothesis postulates that some brain regions; such as the hippocampus; are inherently more vulnerable to brain injury than others. We propose to test these hypotheses in mice with closed head injury; an animal model of blunt head trauma. Regional changes in NMDAR availablility and functional (activational) state will be measured at times ranging from 5 min to 60 days after injury using quantitative autoradiography of the use-dependent ligand MK801. Physiological correlates of NMDAR hyepr-activation and hypo-activation will be measured using electrophysiology (Long term potentiation). Cognitive deficits will be tested 14 and 60 days after the injury using two different tasks; the object recognition test and the Morris water maze in animals administered with the full agonist NMDA , the partial NMDAR agonist d-Cycloserine or the antagonist MK801 at various time points and frequencies after the injury. Finally the contribution of several likely mechanisms to the dynamic changes in NMDAR after brain injury will be investigated by 1. Dose response and kinetic studies of the relationship between dose and duration of NMDAR activation and functional respone 2. Manipulating assay conditions 3. immuno-histochemical staining for the obligatory NR1 unit and the NR2 subunits of NMDAR. The proposed research focuses on the fate of NMDAR, a molecule believed to play a key role in the pathology of brain injury. Brain injury is a major public health problem since it is associated with death and long-term disability in a significant proportion of victims, who are mostly young adults. The results may explain the failure of NMDAR antagonists in clinical trials and suggest novel strategies for treatment of brain injury.