Function and Property of Extrasynaptic NMDAR in Neuronal Cell Death

描述（由申请人提供）：急性脑损伤期间大量谷氨酸释放导致n -甲基d -天冬氨酸受体（NMDAR）过度激活，是缺血性卒中和脑外伤中神经元丢失的主要机制。虽然NMDAR的适当激活是细胞存活所必需的，但NMDAR的过度激活会刺激细胞死亡信号并导致钙稳态的丧失。将NMDAR作为缺血性脑卒中和其他形式的神经退行性疾病的治疗干预手段有很大的兴趣和需求。由于普遍抑制所有NMDAR功能可能对正常脑功能有害，针对特定的NMDAR池或亚型可能提高治疗价值。例如，抑制突触外NMDAR可以在不破坏正常突触功能的情况下减弱受体的过度激活。我们假设突触性NMDAR和突触外NMDAR的药理学性质有显著差异。为了验证这一假设并更好地了解突触外NMDAR功能，我们将追求3个具体目标：目的1)确定突触外NMDAR在细胞死亡中的功能；目的2)确定突触外NMDAR在Ca异常中的作用；目的3)确定突触外NMDAR与突触外NMDAR在药理学性质上的差异。本应用建议利用钙成像和分子表征来鉴定突触外NMDAR的功能和性质。该建议的结果有望为未来通过特异性阻断神经突触外NMDAR来减轻神经退行性疾病（如中风）的治疗策略奠定基础。

DESCRIPTION (provided by applicant): Overactivation of N-methyl D-aspartate receptor (NMDAR) by massive glutamate release during acute brain insults represents a major mechanism for neuronal loss in ischemic stroke and brain trauma. While proper activation of NMDAR is required for cell survival, overactivation of NMDAR stimulates cell death signaling and causes the loss of calcium homeostasis. There are significant interests and needs to target NMDAR as therapeutic interventions for ischemic stroke and other forms of neurodegeneration. Because general suppression of all NMDAR function may be detrimental to normal brain functions, targeting specific pools or subtypes of NMDAR may improve the therapeutic values. For example, inhibiting extrasynaptic NMDAR may attenuate receptor overactivation without disrupting normal synaptic functions. We hypothesize that the pharmacological property is dramatically different between synaptic and extrasynaptic NMDAR. To test the hypothesis and better understand the function of extrasynaptic NMDAR function, we will pursue 3 specific aims: Aim 1) Determine the function of extrasynaptic NMDAR in cell death; Aim 2) Determine the function of extrasynaptic NMDAR in Ca dysregulation; Aim 3) Determine the difference in pharmacological property between extrasynaptic and synaptic NMDAR. This application proposes to use calcium imaging and molecular characterization to identify the function and property of extrasynaptic NMDAR. The outcome of this proposal is expected to set the foundation for future therapeutic strategies to attenuate neurodegeneration, such as stroke, via specific blockade of extrasynaptic NMDAR. PUBLIC HEALTH RELEVANCE: Stroke is one of the major causes of mortality and adult disability in the United States. The long-term goal of our research is to develop molecular therapies for stroke. In addition, our study on molecular and cellular mechanisms may also lead to therapeutic development for other forms of neurodegeneration.