AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

项目总结/摘要 组1（Gp 1）代谢型谷氨酸受体的激活导致内源性谷氨酸受体的强烈升高。 海马兴奋性神经元的兴奋性。另一方面，Gp 1 mGluR活性异常升高， 在多种神经系统疾病与共病癫痫中观察到。尽管有这些意见， Gp 1 mGluRs激活后内在兴奋性和癫痫发作活动升高的机制 仍然不清楚。通过家长奖的支持，我们最近的研究发现， 抑制性p53与体外神经元兴奋性和体内癫痫易感性正相关。 因为我们的最新数据表明，在Gp 1 mGluR表达的情况下，p53蛋白水平和转录活性上调， 激活，我们假设Gp 1 mGluRs的激活促进神经元的内在兴奋性和癫痫发作， 部分通过p53的活性。在目的1中，我们建议研究p53活性的分子调控， Gp 1 mGluR的激活。在目的2中，我们建议确定p53对Gp 1 mGluR诱导的细胞凋亡的贡献。 神经元内在兴奋性升高。在目的3中，我们提出评估p53在Gp 1 mGluR中的作用。 相关的体内癫痫发作活性。我们期望这个项目能（1）为有前途的研究生提供培训 （2）阐明Gp 1 mGluR-1的激活机制。 诱导神经元过度兴奋，这是在目标2.3的范围内的母奖项;和（3）扩大 我们对中枢神经系统中p53的基本理解，这与目标3.3直接相关 家长奖。

PROJECT SUMMARY/ABSTRACT Activation of group 1 (Gp1) metabotropic glutamate receptors leads to robust elevation of intrinsic excitability of hippocampal excitatory neurons. Abnormally elevated activity of Gp1 mGluR, on the other hand, has been observed in multiple neurological disorders with comorbid epilepsy. Despite these observations, the mechanisms underlying elevated intrinsic excitability and seizure activity following activation of Gp1 mGluRs remain unclear. Through the support of the parent award, our recent studies discovered that the activity of tumor suppressor p53 is positively correlated with neuronal excitability in vitro and seizure susceptibility in vivo. Because our latest data showed an up-regulation of p53 protein levels and transcription activity upon Gp1 mGluR activation, we hypothesize that activation of Gp1 mGluRs promotes neuronal intrinsic excitability and seizure activity in part through p53. In Aim 1, we propose to study the molecular regulation of p53 activity following activation of Gp1 mGluR. In Aim 2, we propose to determine the contribution of p53 to Gp1 mGluR-induced elevation of neuronal intrinsic excitability. In Aim 3, we propose to evaluate the role of p53 in Gp1 mGluR- associated seizure activity in vivo. We expect this project to (1) provide training to a promising graduate student who came from a disadvantaged background, (2) elucidate the mechanism underlying activation of Gp1 mGluR- induced neuronal hyperexcitability, which is within the scope of Aim 2.3 of the parent award; and (3) broaden our fundamental understanding of p53 in the central nervous system, which is directly associated with Aim 3.3 of the parent award.