The Dynamics of Excitatory Neurotransmission

从我们的感官体验到我们的明显行为，以及在这之间发生的所有复杂的认知过程，这些基本的生物学决定了我们是谁，这些生物学决定了我们是谁。谷氨酸是大脑中最丰富的神经递质，占大脑内快速信息处理的绝大部分。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相邻神经元上的受体。为了实现具有高信噪比的快速有效的通信，谷氨酸必须在其初始释放后的毫秒内从细胞外空间中去除。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，即快速的谷氨酸摄取促进有效的通信和细胞生长，而过量或长期的细胞外谷氨酸水平对大脑中的细胞功能和信息处理有害。如果谷氨酸转运体系统崩溃，我们的记忆，我们的经验和精神敏锐度，以及几乎所有其他使我们成为我们的东西。ApproachRecent研究质疑标准实验室测定的生理相关性，该测定通常用于量化谷氨酸摄取，并表明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蛋白。我的研究计划将使用最先进的成像方法，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管理保持对神经元之间的严格控制健康大脑中的神经元通信。我们的目标是了解某些大脑区域在科普神经活动期间释放的高水平谷氨酸盐的能力方面的差异，以及这一过程如何影响脑细胞相互“交谈”的效率。新奇和预期意义的发现预计这项工作将揭示大脑中构成谷氨酸转运体系统的特定蛋白质的重要作用。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，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，以更好地了解中枢神经系统功能的最基本方面之一。

BackgroundThe 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. ApproachRecent 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 findingsIt 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.