Restoration of plasticity after pediatric traumatic brain injury

描述(申请人提供)：创伤性脑损伤(TBI)是导致儿童和青少年死亡和残疾的最重要的单一原因，但对儿童脑损伤与成人脑损伤的潜在机制知之甚少。据了解，未成熟脑的创伤性生物力学损伤可表现为慢性认知和行为问题，并丧失发育潜力。可塑性被定义为大脑修改细胞和网络结构和功能以应对环境变化的一种机制。越来越多的证据表明，儿童脑外伤可导致神经传递的可塑性受损和改变。谷氨酸是中枢神经系统的主要兴奋性神经递质，与颅脑损伤的急性病理生理密切相关，但对正常发育和神经可塑性也是至关重要的。这项应用建议研究未成熟大脑对脑损伤的谷氨酸能反应，特别是涉及N-甲基-D-天冬氨酸(NMDA)受体的反应。这一建议的中心假设是，NMDA受体功能障碍是发育性脑损伤后可塑性丧失的基础，这种干扰可以通过分子(特定目标1和2)、电生理学(特定目标3)和认知(特定目标4)来测量，使用一个描述良好的儿科脑损伤实验模型。通过确定损伤后这一重要神经递质系统的变化时间进程，将有可能确定NMDA受体的神经反应受损的窗口。对这一时间段的正确识别将指导这一应用的最终目标(特定目标5)，即利用增强NMDA受体神经传递的药理学药物来使发育中的大脑的分子轮廓正常化，并缓解行为和认知缺陷。这一建议提供了一个独特的机会，可以严格测试一种针对年龄的治疗策略，该策略旨在为最容易受到脑外伤的儿童患者群体带来好处。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the single most important cause of death and disability in children and adolescents, yet relatively little is known about the underlying mechanisms that distinguish pediatric brain injury from that in adults. It is understood the traumatic biomechanical injury to the immature brain can manifest as chronic cognitive and behavioral problems with a loss of developmental potential. Plasticity is defined as a mechanism by which the brain modifies cellular and network structure and function to respond to changes in the environment. There is increasing evidence that pediatric TBI can result in impaired plasticity and alterations in neurotransmission. Glutamate represents the major excitatory neurotransmitter in the central nervous system and is intimately involved in the acute pathophysiology of TBI, but also is critical for normal development and for neural plasticity. This application proposes to investigate the glutamatergic response to TBI in the immature brain, in particular, that which involves the N-methyl-D-aspartate (NMDA) receptor. The central hypothesis of this proposal is that dysfunction at the NMDA receptor underlies the loss of plasticity seen following developmental TBI, and that this perturbation can be measured molecularly (Specific Aims 1 and 2), electrophysiologically (Specific Aim 3) and cognitively (Specific Aim 4), using a well-characterized experimental model of pediatric TBI. By determining the post-injury time course of changes in this important neurotransmitter system, it will be possible to identify the window of impaired neural responsiveness at the NMDA receptor. Proper identification of this time period will then direct the final aim (Specific Aim 5) of this application, which is to utilize pharmacological agents that augment NMDA receptor neurotransmission to normalize the molecular profile of the developing brain and to alleviate behavioral and cognitive deficits. This proposal provides a unique opportunity to rigorously test an age-specific therapeutic strategy that is designed to be beneficial for the patient population most vulnerable to TBI, children.