The Dynamics of Excitatory Neurotransmission

兴奋性神经传递的动力学

• 批准号: RGPIN-2016-03940
• 负责人: Parsons, Matthew
• 金额: $ 2.62万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=661638
• 关键词: Dynamics; Excitatory; Neurotransmission

Background***The underlying biology that makes us who we are — from our sensory experiences to our overt behaviours and all of the complex cognitive processing that occurs in between — critically relies on the neurotransmitter glutamate. Glutamate is the brain's most abundant neurotransmitter and accounts for the large majority of rapid information processing within the brain. For brain cells to communicate with each other, glutamate is typically first released from one neuron into the extracellular space where it can act on receptors that are located on a neighbouring neuron. In order to achieve rapid and efficient communication with a high signal-to-noise ratio, glutamate must be removed from the extracellular space within milliseconds following its initial release. This is accomplished through the glutamate transporter system, which is responsible for the uptake of glutamate from the extracellular space back into neurons and other supporting cells. The importance of understanding the glutamate transporter system is highlighted by the well-accepted view that rapid glutamate uptake promotes effective communication and cellular growth whereas excessive or prolonged levels of extracellular glutamate is detrimental to cellular function and information processing in the brain. If the glutamate transporter system breaks down, so do our memories, our experiences and mental acuity, as well as virtually everything else that makes us who we are. ***Approach***Recent research calls into question the physiological relevance of a standard laboratory assay that is commonly used to quantify glutamate uptake and suggests that novel strategies must be employed to study glutamate transporters in living tissue under endogenous release conditions. My research program will use a state-of-the-art imaging approach combined with recordings of the electrical activity of brain cells to understand the glutamate transporter system and how it manages to maintain strict control over neuron-to-neuron communication in the healthy brain. We aim to understand how certain brain regions differ in their ability to cope with the high level of glutamate that is released during neural activity and how this process affects the efficiency with which brain cells “talk” to each other. ***Novelty and expected significance of findings***It is expected that this work will uncover important roles of the specific proteins in the brain that constitute the glutamate transporter system. While this work may have downstream applications related to the declining nervous system function that occurs, for example, in aging and neurodegenerative disease, the proposed research program aims to address the research challenge of quantifying glutamate uptake in a physiologically-relevant and feasible way in an effort to gain a better understanding of one of the most fundamental aspects of central nervous system function.**

从我们的感官体验到我们的显性行为，以及在这两者之间发生的所有复杂的认知过程，这些决定我们是谁的潜在生物学，都严重依赖于神经递质谷氨酸。谷氨酸是大脑中最丰富的神经递质，在大脑的快速信息处理中占绝大多数。为了使脑细胞相互交流，谷氨酸通常首先从一个神经元释放到细胞外空间，在那里它可以作用于位于邻近神经元上的受体。为了实现高信噪比的快速高效通信，谷氨酸必须在最初释放后的几毫秒内从细胞外空间去除。这是通过谷氨酸转运体系统完成的，该系统负责将谷氨酸从细胞外空间摄取回神经元和其他支持细胞。理解谷氨酸转运体系统的重要性被广泛接受的观点所强调，即谷氨酸的快速摄取促进了有效的通讯和细胞生长，而过量或长时间的细胞外谷氨酸水平不利于细胞功能和大脑的信息处理。如果谷氨酸转运系统崩溃，我们的记忆、经验和精神敏锐度，以及几乎所有决定我们是谁的东西也会崩溃。最近的研究对通常用于量化谷氨酸摄取的标准实验室检测的生理相关性提出了质疑，并建议必须采用新的策略来研究内源性释放条件下活组织中的谷氨酸转运体。我的研究项目将使用最先进的成像方法，结合脑细胞电活动的记录，来了解谷氨酸转运系统，以及它如何在健康的大脑中严格控制神经元间的通讯。我们的目标是了解某些大脑区域在处理神经活动中释放的高水平谷氨酸的能力上是如何不同的，以及这个过程是如何影响脑细胞彼此“交谈”的效率的。***研究结果的新颖性和预期意义***预计这项工作将揭示构成谷氨酸转运系统的特定蛋白质在大脑中的重要作用。虽然这项工作可能具有与神经系统功能下降相关的下游应用，例如在衰老和神经退行性疾病中发生，但拟议的研究计划旨在解决以生理相关和可行的方式量化谷氨酸摄取的研究挑战，以更好地理解中枢神经系统功能的最基本方面之一