Abstract Mammalian brains are extremely sensitive to metabolic perturbation. If blood glucose drops by only a factor of ~2, immediate neurological symptoms emerge, including delirium and coma. We identified nerve terminals as a one of the likely loci of this vulnerability, as the vesicle recycling program crashes very quickly upon fuel withdrawal. We hypothesize that this metabolic sensitivity may lie at the heart of both neurodegenerative and neuropsychiatric diseases, as brain hypometabolism is a strong predictor of the onset of these diseases (albeit on different time scales). We seek to address many fundamental knowledge gaps we have concerning how local synaptic metabolism is regulated, including what molecular machineries for metabolism support synapse function and how different metabolic fuels can be used to support synapse function. We recently determined that one of the ten enzymes needed for glycolysis serves as a critical control point for glycolytic flux in nerve terminals. Enhancing the activity of his enzyme, PGK-1, only 2-fold is sufficient to provide dramatic protection against hypometabolic synaptic dysfunction. We recently discovered that synapses contain the necessary machinery to both synthesize and utilize lipid droplets, and that they normally constantly burn through these lipid droplets to sustain synapse function. Mutations in the key triglyceride lipase required to lipid droplet use are drivers of neurological disease, including intellectual disability. Similarly, we have recently uncovered a new role for neuromodulators at nerve terminals: in addition to directly controlling synapse function, they serve as signals to tell synapses to either store or use glycogen. Our aims to examine how difference cell biological machineries in synapses allow fuel switching and how perturbations in these machineries drive or heighten neurological disease states.