AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

项目摘要/摘要 激活第1组(Gp1)代谢性谷氨酸受体导致内源性升高 海马兴奋性神经元的兴奋性。另一方面，Gp1 mGluR活性异常升高， 已在多种神经系统疾病中观察到，并伴有癫痫。尽管有这些观察，但 Gp1 mGluRs激活后内源性兴奋性和惊厥活性升高的机制 目前仍不清楚。通过家长奖的支持，我们最近的研究发现，肿瘤的活性 抑癌基因P53与体外神经元兴奋性和体内癫痫敏感性呈正相关。 因为我们的最新数据显示Gp1 mGluR上的P53蛋白水平和转录活性上调 激活，我们假设Gp1 mGluRs的激活促进神经元的内在兴奋性和癫痫发作 活性部分通过P53来实现。在目标1中，我们建议研究P53活性的分子调控 激活Gp1 mGluR。在目标2中，我们建议确定P53在Gp1 mGluR诱导中的作用 神经元内在兴奋性的升高。在目标3中，我们建议评估P53在Gp1 mGluR中的作用。 活体内相关的癫痫活动。我们希望这个项目(1)为有前途的研究生提供培训 (2)阐明Gp1 mGluR激活的机制。 诱导的神经元超兴奋性，这在父母奖的目标2.3的范围内；和(3)扩大 我们对中枢神经系统中P53的基本理解，它与AIM 3.3直接相关 家长奖的获奖者。

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.