Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation

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.