Glucose sparing by glycogenolysis (GSG) determines the relationship between brain metabolism and neurotransmission

Over the last two decades, it has been established that glucose metabolic fluxes in neurons and astrocytes are proportional to the rates of the glutamate/GABA-glutamine neurotransmitter cycles in close to 1:1 stoichiometries across a wide range of functional energy demands. However, there is presently no mechanistic explanation for these relationships. We present here a theoretical meta-analysis that tests whether the brain's unique compartmentation of glycogen metabolism in the astrocyte and the requirement for neuronal glucose homeostasis lead to the observed stoichiometries. We found that blood-brain barrier glucose transport can be limiting during activation and that the energy demand could only be met if glycogenolysis supports neuronal glucose metabolism by replacing the glucose consumed by astrocytes, a mechanism we call Glucose Sparing by Glycogenolysis (GSG). The predictions of the GSG model are in excellent agreement with a wide range of experimental results from rats, mice, tree shrews, and humans, which were previously unexplained. Glycogenolysis and glucose sparing dictate the energy available to support neuronal activity, thus playing a fundamental role in brain function in health and disease.