Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, glucose levels in the brain plummet, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program that induces the expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo . We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by powering the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 ensures the metabolic plasticity of synaptic transmission.
Highlights: Glucose deprivation drives transcriptional reprogramming of neuronal metabolism via CREB and PGC1α. Glucose or food deprivation trigger the neuronal expression of mitochondrial deacetylase sirtuin 3 (Sirt3) both in vitro and in vivo . Sirt3 stimulates oxidative ATP synthesis in nerve terminals.Sirt3 sustains the synaptic vesicle cycle in the absence of glucose.