The Dynamics of Excitatory Neurotransmission

背景*决定我们是谁的潜在生物学，从我们的感觉体验到我们的公开行为，以及在这两者之间发生的所有复杂的认知过程，关键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，占大脑中快速信息处理的绝大多数。为了让脑细胞相互交流，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邻近神经元上的受体。为了在高信噪比的情况下实现快速、有效的通讯，谷氨酸必须在最初释放后的几毫秒内从细胞外空间中移除。这是通过谷氨酸转运蛋白系统完成的，该系统负责将谷氨酸从细胞外空间吸收回神经元和其他支持细胞。人们普遍认为，快速摄取谷氨酸可促进有效的沟通和细胞生长，而细胞外过多或长时间的谷氨酸水平不利于细胞功能和大脑中的信息处理，这一观点突显了了解谷氨酸转运蛋白系统的重要性。如果谷氨酸转运体系统崩溃，我们的记忆、我们的经历和精神敏锐度也会崩溃，几乎所有造就我们的东西都会崩溃。*方法**最近的研究对通常用于量化谷氨酸摄取的标准实验室测试的生理学相关性提出了质疑，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一种最先进的成像方法，结合脑细胞电活动的记录，以了解谷氨酸转运蛋白系统，以及它如何设法保持对健康大脑中神经元之间的通信的严格控制。我们的目标是了解某些大脑区域在应对神经活动过程中释放的高水平谷氨酸的能力方面有何不同，以及这一过程如何影响脑细胞相互“交谈”的效率。*发现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体系统的大脑中特定蛋白质的重要作用。虽然这项工作可能有与神经系统功能下降有关的下游应用，例如在衰老和神经退行性疾病中，但拟议的研究计划旨在解决以与生理相关和可行的方式量化谷氨酸摄取的研究挑战，以努力更好地了解中枢神经系统功能的最基本方面之一。

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.**