The Role of CaMKII Binding to NMDA-Rs in LTP

CaMKII 与 NMDA-R 结合在 LTP 中的作用

• 批准号: 7223698
• 负责人: Robert F Dallapiazza
• 金额: $ 2.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223698
• 关键词: AMPA receptors; NMDA receptors; age difference; brain electrical activity; calmodulin dependent protein kinase; enzyme activity; evoked potentials; gene expression; gene mutation; genetically modified animals; hippocampus; laboratory mouse; long term potentiation; neural transmission; predoctoral investigator; protein binding; protein protein interaction; receptor binding; synapses; tissue /cell culture

DESCRIPTION (provided by applicant): Synapses are highly dynamic structures that are capable of enhancing or depressing their efficiency based on the pattern and intensity of their stimuli. This process is termed synaptic plasticity. The most frequently studied form of synaptic plasticity is long-term potentiation (LTP) in the CA 1 region of the hippocampus. The main goal of this project is to further understand the molecular mechanisms of LTP. The induction of LTP is critically dependent on the activation of N-methyl-D-aspartate-type glutamate receptors (NMDA-R) and Ca2+/Calmodulin-Dependent Kinase II (CaMKII). These two signaling molecules interact in an activity- dependent fashion through the cytosolic tails of two NMDA-R subunits NR1 and NR2B. These interactions are believed to recruit CaMKII to active postsynaptic signaling sites where it is thought to play a crucial role in orchestrating the molecular changes that accompany synaptic plasticity. Our laboratory has developed two strains of mice with targeted mutations to NR1 and NR2B that are deficient in their ability to bind to CaMKII. These strains of mice will be used to test the significance of CaMKII recruitment to these binding sites during LTP. I will use electrophyiological and Ca2+ imagining studies to characterize the effects of the targeted NR1 and NR2B point mutations on basal synaptic transmission and synaptic plasticity. The results of these studies will provide clear evidence to the importance of NMDA-R mediated CaMKII recruitment to the postsynaptic density during the induction of synaptic plasticity. These studies crucial for understanding physiologic changes in synaptic function, as in associative learning, and in pathological states involving synaptic changes including neurodegenerative diseases, psychiatric diseases, and cerebral ischemia. Mental wellbeing is emerging as one of the most important areas in public health. The results from our study will significantly contribute to our knowledge of synaptic transmission, which has been implicated in a wide range of mental health diseases including depression, substance abuse, and schizophrenia.

描述（由申请人提供）：突触是高度动态的结构，能够根据刺激的模式和强度提高或降低其效率。这个过程被称为突触可塑性。最常研究的突触可塑性形式是海马 CA 1 区域的长时程增强 (LTP)。该项目的主要目标是进一步了解LTP的分子机制。 LTP 的诱导主要依赖于 N-甲基-D-天冬氨酸型谷氨酸受体 (NMDA-R) 和 Ca2+/钙调蛋白依赖性激酶 II (CaMKII) 的激活。这两种信号分子通过两个 NMDA-R 亚基 NR1 和 NR2B 的胞质尾部以活性依赖性方式相互作用。这些相互作用被认为将 CaMKII 招募到活跃的突触后信号传导位点，在协调伴随突触可塑性的分子变化方面发挥着至关重要的作用。我们的实验室开发了两种具有 NR1 和 NR2B 靶向突变的小鼠品系，它们缺乏与 CaMKII 结合的能力。这些小鼠品系将用于测试 LTP 期间 CaMKII 募集到这些结合位点的重要性。我将使用电生理学和 Ca2+ 成像研究来表征靶向 NR1 和 NR2B 点突变对基础突触传递和突触可塑性的影响。这些研究的结果将为突触可塑性诱导过程中 NMDA-R 介导的 CaMKII 募集对突触后密度的重要性提供明确的证据。这些研究对于理解突触功能的生理变化（如联想学习）以及涉及突触变化的病理状态（包括神经退行性疾病、精神疾病和脑缺血）至关重要。心理健康正在成为公共卫生中最重要的领域之一。我们的研究结果将极大地增进我们对突触传递的认识，突触传递与多种精神健康疾病有关，包括抑郁症、药物滥用和精神分裂症。