Energy is important for maintaining the function of synapses and for fueling changes in synaptic activity. Such synaptic plasticity requires local energy production. The mechanism by which metabolic pathways are regulated to locally respond to the changing energy demands at synapses is not well understood. Through a forward genetic screen, we identified a metabolic enzyme, phosphofructokinase-1/pfk-1.1, as important for maintaining synaptic vesicle clustering under energy stress (e.g. hypoxia and neuronal stimulation). Through genetic analysis and fluorescence recovery after photobleaching (FRAP), the disruption of synaptic vesicle clustering was found to be due to disrupted synaptic vesicle cycling. This phenotype was observed in all the neurons examined: C. elegans motor neurons, interneuron AIY, and the serotonergic NSM neuron. We demonstrate that pfk-1.1, a rate-limiting enzyme in the glycolysis pathway, acts cell autonomously and that other glycolytic mutants also are required for maintaining synaptic vesicle cycling under energy stress. In addition, we observe that glycolytic enzymes cluster perisynaptically in response to energy stress, suggesting that a transient glycolysis compartment, or ‘glycolytic metabolon’, forms in order to generate energy locally. We also observe that the formation of the glycolytic metabolon is dependent on the central metabolic regulator, AMP-kinase. Finally, we demonstrate that pfk-1.1 mutant animals have impaired synaptic recovery and locomotion under energy stress. Our studies indicate that energy demands in neurons are met locally through the assembly of a glycolytic metabolon to sustain synaptic function and behavior.
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