Project description
Bioenergetics of synaptic transmission
Synaptic transmission is an energy-dependent process that consumes up to 75 % of the total energy required for brain function. The metabolic pathways of ATP production have been studied in detail, but actual molecular regulation of synaptic bioenergetics, and how synapses obtain the required amount of ATP, is poorly understood. The EU-funded SynaptoEnergy project aims to investigate molecular mechanisms controlling energy pathways in firing synapses. The working hypothesis of the project is that there are presynaptic tightly regulated control mechanisms enabling molecular activation of the glycolysis and the oxidative phosphorylation on demand coupling local ATP synthesis to required level of consumption. The research will utilise cutting-edge optophysiology tools to study neuronal bioenergetics together with novel proteomics approaches to identify key molecular players involved in controlling presynaptic energy production.
Objective
Synaptic transmission is an extremely energetically-demanding process that consumes 75% of the energy required for brain function. However, it remains poorly understood how synapses guarantee the necessary ATP levels required for neurotransmission. While our understanding of the metabolic pathways for ATP production is vastly detailed, very little is known about the actual molecular implementation of these pathways in neurons for sustaining synaptic bioenergetics. I hypothesize that tightly-regulated control mechanisms exist presynaptically to ensure the molecular activation of glycolysis and oxidative phosphorylation (OxPhos) on demand, optimally coupling local ATP synthesis to consumption thereby maintaining synaptic metabolic integrity and safeguarding presynaptic function. Here I propose to develop a comprehensive molecular understanding of the mechanisms controlling these pathways in firing synapses. I will use cutting-edge optophysiology tools that I and others have developed to study neuronal bioenergetics together with novel proteomic approaches to identify key molecules involved in controlling presynaptic OxPhos and glycolysis. First, I will dissect the fundamental mechanisms controlling Ca2+-mediated activation of OxPhos in presynaptic mitochondria during synaptic activity. To further elucidate the presynaptic choreography of molecular mechanisms enhancing glycolysis rates on demand, I will dissect the mechanistic control of the presynaptic glucose carrier GLUT4 and establish the role of glycolytic metabolons in accelerating glycolysis during synaptic activity. By generating for the first time a comprehensive picture of the molecular mechanisms actively maintaining presynaptic metabolic integrity, this study will provide a framework for future studies into the molecular basis of brain disease states associated with dysfunctional metabolism, such as mitochondriopathies, vascular dementias or glucose metabolism diseases.
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Funding Scheme
ERC-STG - Starting GrantHost institution
75013 Paris
France