Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations

Lactate shuttled from the blood circulation, astrocytes, oligodendrocytes or even activated microglia (resident macrophages) to neurons has been hypothesized to represent a major source of pyruvate compared to what is normally produced endogenously by neuronal glucose metabolism. However, the role of lactate oxidation in fueling neuronal signaling associated with complex cortex function, such as perception, motor activity, and memory formation, is widely unclear. This issue has been experimentally addressed using electrophysiology in hippocampal slice preparations (ex vivo) that permit the induction of different neural network activation states by electrical stimulation, optogenetic tools or receptor ligand application. Collectively, these studies suggest that lactate in the absence of glucose (lactate only) impairs gamma (30-70 Hz) and theta-gamma oscillations, which feature high energy demand revealed by the cerebral metabolic rate of oxygen (CMRO2, set to 100%). The impairment comprises oscillation attenuation or moderate neural bursts (excitation-inhibition imbalance). The bursting is suppressed by elevating the glucose fraction in energy substrate supply. By contrast, lactate can retain certain electric stimulus-induced neural population responses and intermittent sharp wave-ripple activity that features lower energy expenditure (CMRO2 of about 65%). Lactate utilization increases the oxygen consumption by about 9% during sharp wave-ripples reflecting enhanced adenosine-5'-triphosphate (ATP) synthesis by oxidative phosphorylation in mitochondria. Moreover, lactate attenuates neurotransmission in glutamatergic pyramidal cells and fast-spiking, γ-aminobutyric acid (GABA)ergic interneurons by reducing neurotransmitter release from presynaptic terminals. By contrast, the generation and propagation of action potentials in the axon is regular. In conclusion, lactate is less effective than glucose and potentially detrimental during neural network rhythms featuring high energetic costs, likely through the lack of some obligatory ATP synthesis by aerobic glycolysis at excitatory and inhibitory synapses. High lactate/glucose ratios might contribute to central fatigue, cognitive impairment, and epileptic seizures partially seen, for instance, during exhaustive physical exercise, hypoglycemia and neuroinflammation.