The Dynamics of Excitatory Neurotransmission

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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.