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。在美国，每年有超过10万名儿童因创伤性脑损伤入院，还有更多的病例要么没有入院，要么没有得到医疗关注。相当数量的头部受伤儿童会发展成持续性的行为或认知障碍。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中介是N-甲基-D-天冬氨酸受体(NMDAR)，它的激活对于正常的大脑成熟和经验依赖的可塑性至关重要。NMDAR亚基组成在发育性脑损伤后发生了深刻的变化(见初步研究2)。因此，提出以下假设：1)脑损伤后NMDAR结构成分的改变将导致NMDAR功能受损；2)发育性脑损伤后NMDAR功能受损将导致成熟脑的解剖学改变。为了解决这些假设，NMDAR亚单位的变化将使用基因和蛋白质表达的分子测量方法在创伤损伤的未成熟脑中定位。NMDAR功能障碍将直接在这些区域进行评估，方法是测量长期增强的诱导和NMDA介导的钙离子流量。最后，对创伤诱导的NMDAR功能障碍的晚期后遗症的研究将利用一种新的组合，即发育性脑震荡和在丰富的环境(EE)中养育所诱导的经验依赖性可塑性。在发育中的脑损伤和胚胎发育过程中，树突和突触的分子标志物的持续变化以及树突树本身的结构变化可能在成年期表现出来。这项研究将为脑损伤提供一个不同的视角，通过关注损伤引起的神经元功能障碍而不是细胞死亡，在一个持续发展的环境中，暂时的损伤可以转化为永久性的缺陷。

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.