NMDA receptor dysfunction after traumatic brain injury

描述（由申请人提供）：创伤性脑损伤（TBI）是美国儿科死亡和残疾的头号原因。儿科TBI占美国每年住院人数超过10万人，更多的病例要么不入院，要么不就医。相当数量的头部受伤的儿童发展为持久的行为或认知障碍。这些后遗症的潜在机制可能是广泛的神经元功能障碍，而不是细胞死亡。这些缺陷的一个可能的介质是N-甲基-D-天冬氨酸受体（NMDAR），其激活对于正常的大脑成熟和经验依赖的可塑性至关重要。发育性TBI后，NMDAR亚基组成发生深刻变化（见初步研究2）。因此，提出以下假设：1）TBI后NMDAR结构组成的变化将导致NMDAR功能受损，以及2）发育TBI后NMDAR功能受损将导致成熟脑中的解剖学变化。为了解决这些假设，NMDAR亚基的变化将使用基因和蛋白质表达的分子测量在创伤性损伤的未成熟脑中进行区域定位。然后通过测量长时程增强和NMDA介导的钙流的诱导，直接在这些区域评估NMDAR功能障碍。最后，调查创伤引起的NMDAR功能障碍的晚期后遗症将利用一种新的组合，发育脑震荡，然后通过在丰富的环境（EE）中饲养引起的经验依赖性可塑性。发育TBI和EE饲养后，树突和突触的分子标记物的持久变化，以及树突树本身的结构改变，可能会在成年期表现出来。这项研究将提供一个不同的角度对头部损伤的重点是损伤引起的神经元功能障碍，而不是细胞死亡，在一个正在进行的发展，暂时的损害可以转化为永久性的赤字设置。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the number one cause of pediatric death and disability in the U.S. Pediatric TBI accounts for over 100,000 annual U.S. hospital admissions, and many more cases either are not admitted or do not come to medical attention. A significant number of head-injured children develop lasting behavioral or cognitive impairment. The underlying mechanism for these sequelae may be widespread neuronal dysfunction, rather than cell death. One likely mediator of these deficits is the N-methyl-D-aspartate receptor (NMDAR), whose activation is of vital importance for normal brain maturation and experience-dependent plasticity. NMDAR subunit composition is profoundly altered after developmental TBI (see Preliminary Study 2). Therefore, the following hypotheses are proposed: 1) Post-TBI changes in NMDAR structure composition will result in impaired NMDAR function and 2) Impaired NMDAR function following developmental TBI will result in anatomical changes in the mature brain. To address these hypotheses, NMDAR subunit changes will be regionally localized in the traumatically injured immature brain using molecular measures of gene and protein expression. NMDAR dysfunction will then be assessed directly in these regions, by measuring induction of long-term potentiation and NMDA-mediated calcium flux. Finally, investigations into late sequelae of traumatically induced NMDAR dysfunction will utilize a novel combination of developmental concussion followed by experience-dependent plasticity induced by rearing in an enriched environment (EE). After developmental TBI and EE rearing, lasting changes in molecular markers for dendrites and synapses, as well as structural alterations in the dendritic trees themselves, may be manifest in adulthood. This study will provide a different perspective on head injury by focusing on injury-induced neuronal dysfunction rather than cell death, in a setting of ongoing development where a temporary impairment can be translated into a permanent deficit.