Glycogenolysis in Cerebral Cortex During Sensory Stimulation, Acute Hypoglycemia, and Exercise: Impact on Astrocytic Energetics, Aerobic Glycolysis, and Astrocyte-Neuron Interactions.

Most glycogen in cerebral cortex is located in astrocytes, and the importance of glycogenolysis for critical functions, including neurotransmission and memory consolidation, is strongly supported by many studies. However, specific mechanisms through which glycogen sustains essential functions remain to be established by rigorous, quantitative studies. Cerebral cortical glycogen concentrations are in the range of 10-12 μmol/g in carefully-handled animals, and the calculated rate of glycogenolysis (CMRglycogen ) during sensory stimulation is approximately 60% that of glucose utilization (CMRglc ) by all cells, with lower rates during acute hypoglycemia and exercise to exhaustion. CMRglycogen is at least fourfold higher when the volume fraction of astrocytes is taken into account. Inclusion of glycogen consumed during sensory stimulation in calculation of the oxygen-glucose index (OGI = CMRO2 /CMRglc , which has a theoretical maximum of 6 when no other substrates are metabolized) reduces OGI from 5.0 to 2.8. Thus, at least 53% of the carbohydrate is not oxidized, suggesting that glycogen mobilization supports astrocytic glycolysis, not neuronal oxidation of glycogen-derived lactate that would cause OGI to exceed 6. Failure of glycogenolysis to dilute the specific activity of lactate formed from blood-borne [6-14 C]glucose indicates compartmentation of glycolytic metabolism of glucose and glycogen and the rapid release from cerebral cortex of glycogen-derived lactate. Together, these findings invalidate the conclusion by others that glycogen-derived lactate is a major fuel for neurons during neurotransmission, memory consolidation, and exercise to exhaustion. Alternative mechanisms, including glucose sparing for neurons, are presented as testable explanations for data interpreted as lactate shuttling.