NMDA receptor dysfunction after traumatic brain injury

描述（由申请人提供）：创伤性脑损伤（TBI）是美国儿童死亡和残疾的头号原因，美国每年有超过10万例儿童TBI住院，更多的病例要么没有入院，要么没有得到医疗照顾。大量头部受伤的儿童会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中介是n -甲基-d -天冬氨酸受体（NMDAR），其激活对正常的大脑成熟和经验依赖的可塑性至关重要。NMDAR亚基组成在发展性脑损伤后发生了深刻的改变（见初步研究2）。因此，我们提出以下假设：1)脑外伤后NMDAR结构组成的改变会导致NMDAR功能受损；2)发展性脑外伤后NMDAR功能受损会导致成熟脑的解剖改变。为了解决这些假设，NMDAR亚基改变将在创伤性损伤的未成熟大脑中使用基因和蛋白质表达的分子测量进行局部定位。然后通过测量长期增强和nmda介导的钙通量的诱导，直接评估这些区域的NMDAR功能障碍。最后，对创伤性NMDAR功能障碍的晚期后遗症的研究将利用发展性脑震荡和在丰富环境（EE）中抚养引起的经验依赖可塑性的新组合。在发育性脑外伤和情感表达后，树突和突触分子标记的持续变化，以及树突树本身的结构改变，可能在成年期表现出来。这项研究将通过关注损伤引起的神经元功能障碍而不是细胞死亡，为头部损伤提供不同的视角，在持续发展的背景下，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.