Abstract
The role of glycogen in the central nervous system is intimately linked with the glycolytic pathway. Glycogen is synthesized from glucose, the primary substrate for glycolysis, and degraded to glucose-6-phosphate. The metabolic cost of shunting glucose via glycogen exceeds that of simple phosphorylation of glucose to glucose-6-phosphate by hexokinase; thus, there must be a metabolic advantage in utilizing this shunt pathway. The dogmatic view of glycogen as a storage depot persists, based on initial descriptions of glycogen supporting neural function in the face of aglycemia. The variable latency to conduction failure, dependent upon tissue glycogen levels, provided convincing evidence of the role played by glycogen in supporting neural function. Glycogen is located predominantly in astrocytes in the central nervous system, thus for glycogen to benefit neural elements, intercellular metabolic communication must exist in the form of astrocyte to neuron substrate transfer. Experimental evidence supports a model where glycogen is metabolized to lactate in astrocytes, with cellular expression of monocarboxylate transporters and enzymes appropriately located for lactate shuttling between astrocytes and neural elements, where lactate acts as a substrate for oxidative metabolism. Biosensor recordings have demonstrated a significant steady concentration of lactate present on the periphery of both central white matter and peripheral nerve under unstimulated baseline conditions, indicating continuous cellular efflux of lactate to the interstitium. The existence of this lactate pool argues we must reexamine the “on demand” shuttling of lactate between cellular elements, and suggests continuous lactate efflux surplus to immediate neural requirements.
Highlights
In the last 20 years interest in brain energy metabolism, and in particular specific cellular substrate utilization and trafficking of metabolites between neural elements and glia has witnessed a rapid growth, which shows no sign of abating
In our rodent optic nerve model we investigated the trafficking of lactate between astrocytes and axons, by investigating the role of glycogen in supporting axon conduction
Biochemical assay revealed that at the onset of aglycemia glycogen content fell and continued to fall until it reached its nadir, which coincided with the loss of the compound action potential (CAP) (Brown et al, 2003a) (Wender et al, 2000). These results showed that tissue glycogen was metabolized and supported axon conduction in the absence of exogenously applied glucose, but that once the glycogen was exhausted the CAP failed
Summary
In the last 20 years interest in brain energy metabolism, and in particular specific cellular substrate utilization and trafficking of metabolites between neural elements and glia has witnessed a rapid growth, which shows no sign of abating. It has recently been shown that the lactate generated in the periphery as a result of maximal exercise is not a waste product after all, and crosses the blood brain barrier where it is oxidatively metabolized by the brain (Dalsgaard, 2006), glucose is still the main energy substrate.
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