Interactions among glucose, lactate and adenosine regulate energy substrate utilization in hippocampal cultures

Glucose is the major energy source during normal adult brain activity. However, it appears that glial-derived lactate is preferred as an energy substrate by neurons following hypoxia-ischemia. We examined factors influencing this switch in energetic bias from glucose to lactate in cultured hippocampal neurons, focusing on the effects of the physiological changes in lactate, glucose and adenosine concentrations seen during hypoxia-ischemia. We show that with typical basal concentrations of lactate and glucose, lactate had no effect on glucose uptake. However, at the concentrations of these metabolites found after hypoxia-ischemia, lactate inhibited glucose uptake. Reciprocally, glucose had no effect on lactate utilization regardless of glucose and lactate concentrations. Furthermore, we find that under hypoglycemic conditions adenosine had a small, but significant, inhibitory effect on glucose uptake. Additionally, adenosine increased lactate utilization. Thus, the relative concentrations of glucose, lactate and adenosine, which are indicative of the energy status of the hippocampus, influence which energy substrates are used. These results support the idea that after hypoxia-ischemia, neurons are biased in the direction of lactate rather than glucose utilization and this is accomplished through a number of regulatory steps.