Defining a Role for GABAB Receptor Signaling in Activation of TORC1 Kinase During Homeostatic Plasticity

定义 GABAB 受体信号传导在稳态可塑性 TORC1 激酶激活中的作用

• 批准号: 1724812
• 负责人: Kimberly Raab-Graham
• 金额: $ 17.92万
• 依托单位: Wake Forest University School of Medicine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1724812&HistoricalAwards=false
• 关键词: Defining; Role; GABAB; Receptor; Signaling

Fluctuations in brain neuron activity promote learning and memory. If activity levels remain too high or too low for extended periods of time, the communication between neurons becomes unstable, and, as a consequence, new information cannot be learned. Neurons can alter which proteins are present at specialized sites called synapses, where signals are transmitted from one neuron to another. The way that neurons make these adjustments at the molecular level is poorly understood. Recent work has shown that a protein, referred to as GABAb receptor, causes new proteins to be synthesized by the neuron by a mechanism that involves a second protein, referred to as mTOR. This project will determine how GABAb receptors activate mTOR using cultured rat and mouse neurons. Cultured neurons are the system of choice for visualizing changes in protein synthesis at synapses. The project will determine if the GABAb receptor - mTOR interaction promotes changes in synapse number, which then lead to enhanced communication between neurons. The project will provide training for undergraduates, graduates, and postdoctoral students, including students who are underrepresented in science. It will support development of a new graduate course that trains incoming students in neuroscience laboratory techniques and that gives postdoctoral fellows a formal opportunity to build their teaching skills. Outreach activities are planned through a Community Education Program, Memory Matters.In the brain, mTOR activity regulates protein synthesis, which is essential for learning and memory. Neurons remodel their synapses (plasticity), to accommodate dramatic changes in activity in order to facilitate new learning (homeostasis). One of the most striking examples of homeostatic plasticity is the formation of new synapses when N-methyl-D-aspartate receptor (NMDAR) inputs are blocked, a mechanism thought to require protein synthesis. Recent work from the principal investigator's laboratory has discovered that during NMDAR blockade, GABAb receptors shift from activating post-synaptic potassium channels to increasing L-type calcium channel activity. The rise in calcium channel activity increases mTOR activity in dendrites. This project will use calcium and fluorescent imaging to define the mechanism that shifts GABAb receptor signaling to activate mTOR (Aim 1 and 2). The project will elucidate whether the functional shift of the GABAb receptor is required for structural changes in synapses and synapse number (Aim 3). The project will elucidate whether the functional shift of the GABAb receptor is required for structural changes in synapses and synapse number (Aim 3). This project will offer new insight into molecular mechanisms of homeostatic plasticity.

大脑神经元活动的波动促进学习和记忆。如果活动水平在很长一段时间内保持太高或太低，神经元之间的通信就会变得不稳定，因此无法学习新信息。神经元可以改变哪些蛋白质存在于称为突触的专门部位，信号从一个神经元传递到另一个。神经元在分子水平上进行这些调整的方式还知之甚少。最近的研究表明，一种称为GABAb受体的蛋白质通过涉及第二种蛋白质（称为mTOR）的机制引起神经元合成新的蛋白质。该项目将确定GABAb受体如何使用培养的大鼠和小鼠神经元激活mTOR。培养的神经元是可视化突触蛋白质合成变化的首选系统。该项目将确定GABAb受体- mTOR相互作用是否会促进突触数量的变化，从而增强神经元之间的通信。该项目将为本科生、研究生和博士后学生提供培训，包括在科学领域代表性不足的学生。它将支持开发一门新的研究生课程，培训即将入学的学生学习神经科学实验室技术，并为博士后研究员提供培养教学技能的正式机会。通过社区教育项目“记忆至关重要”计划开展外联活动。在大脑中，mTOR活性调节蛋白质合成，这对学习和记忆至关重要。神经元重塑它们的突触（可塑性），以适应活动的巨大变化，从而促进新的学习（稳态）。稳态可塑性最显著的例子之一是当N-甲基-D-天冬氨酸受体（NMDAR）输入被阻断时新突触的形成，这一机制被认为需要蛋白质合成。主要研究者实验室最近的工作发现，在NMDAR阻断期间，GABAb受体从激活突触后钾通道转变为增加L型钙通道活性。钙通道活性的升高增加树突中的mTOR活性。该项目将使用钙和荧光成像来确定改变GABAb受体信号传导以激活mTOR的机制（目的1和2）。该项目将阐明GABAb受体的功能转变是否是突触和突触数量结构变化所必需的（目标3）。该项目将阐明GABAb受体的功能转变是否是突触和突触数量结构变化所必需的（目标3）。这个项目将提供新的见解的分子机制的稳态可塑性。