NMDA Receptor Dynamics After Brain Injury

描述（由申请人提供）：脑损伤是工业化国家青年人死亡和发病的主要原因。在几个主要的临床试验中，用谷氨酸NMDA受体（NMDAR）拮抗剂治疗意外脑损伤的尝试未能产生任何改善结果。这些试验是基于这样的假设，即头部损伤后的神经功能缺损至少部分是NMDAR过度激活和“兴奋性毒性”的结果。所提出的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.脑损伤后的认知缺陷是NMDA受体激活不足而不是过度激活的结果。3. NMDAR的延迟激活可加速脑损伤后的功能恢复。第二种假设认为，某些大脑区域，如海马体，天生就比其他区域更容易受到脑损伤。我们建议在闭合性头部损伤的小鼠中测试这些假设;钝性头部创伤的动物模型。使用使用依赖性配体MK 801的定量放射自显影术，在损伤后5分钟至60天的时间范围内测量NMDAR可用性和功能（激活）状态的区域变化。将使用电生理学（长时程增强）测量NMDAR高活化和低活化的生理相关性。在损伤后14天和60天使用两个不同的任务测试认知缺陷;在损伤后的不同时间点和频率施用完全激动剂NMDA、部分NMDAR激动剂d-环丝氨酸或拮抗剂MK 801的动物中进行物体识别测试和Morris水迷宫。最后，将通过1. NMDAR激活和功能反应的剂量和持续时间之间关系的剂量反应和动力学研究2.操作测定条件3. NMDAR的专性NR 1和NR 2亚单位的免疫组织化学染色。拟议的研究重点是NMDAR的命运，NMDAR是一种被认为在脑损伤病理学中起关键作用的分子。脑损伤是一个主要的公共卫生问题，因为它与相当大比例的受害者（大多数是年轻人）的死亡和长期残疾有关。这些结果可以解释NMDAR拮抗剂在临床试验中的失败，并为脑损伤的治疗提供新的策略。

DESCRIPTION (provided by applicant): Brain injury is a leading cause of mortality 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.