The brain is famously dependent on a constant supply of fuel in the form of glucose and oxygen and cognitive function is tightly related to metabolic state. The locus of this control is not well understood. Cells make use of fuel by generating a key chemical intermediate called ATP. Information flow in the brain is mediated by transduction of electrical information into chemical information and back again at chemical synapses. Synapses are made up of crucial cellular machineries that orchestrate a balance of membrane traffic to and from the plasma membrane. Our goal is to develop detailed quantitative understanding of the synapse both in terms of physiological responses to action potential stimuli as well as the molecular underpinnings of its function. Synapses are thought to present large ATP demands; however, it is unclear how fuel availability and electrical activity impact synaptic ATP levels and how ATP availability controls synaptic function. We recently developed sensitive approaches that allow us to analyze this problem in detail by measuring the concentration of ATP inside individual nerve terminals. We discovered in this work that synapses function in an Energy on demand mode whereby they synthesize ATP in proportion to the demands being placed on the synapse. Similar findings using different methods were made 2 decades ago regarding heart tissue. The goal of this project is determine the molecular basis of this control system.
The first aim will explore the role the endoplasmic reticulum plays in regulating this energy on demand system. These experiments make use of an emerging technology of genetically-encoded fluorescent indicators that allow one to quantitatively measure how calcium changes in this organelle. It is thought that calcium signals emerging from the endoplasmic reticulum signal mitochondria to make more ATP.
Our second Aim will use another new technology to determine if the carriers of glucose into cells are being redistributed onto the cell surface when neurons become more active
The brain needs a ready supply of fuel that it converts into a molecule that powers almost all of known cell function: this molecule is ATP and fuels must be converted into ATP at synapses so that they can function. The control of this process is not well understood but it is thought that deficiencies in this process likely underlie many forms of neurodegeneration. Our work is aimed at understanding the machinery at a molecular level to better ensure the success of future therapies for many types of neuronal diseases.
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