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

Abstract

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.image

Altered metabolic function induced by amyloid-beta oligomers and PSEN1-mutations in iPSC-derived astrocytes

“…In the brain astrocytes breakdown glycogen under conditions of starvation in order to maintain survival of neurons, protect axons, and ensure synaptic activity is maintained 22 . Furthermore, during neuronal activity uptake of glutamate and NaCl 2 by glutamate transporters in astrocytes initiates glycogenolysis and rapid lactate production 56 , which may be used as a fuel source in neurons (astrocyte-neuron lactate shuttle), although this is still a debated area [57][58][59] . Data presented here shows that glutamate induces glycogenolysis in astrocytes and that process can be blocked using Ouabain and TBOA demonstrating that glutamate uptake and efflux of NaCl 2+ is associated with glycogen breakdown.…”

Brain energy metabolism: A roadmap for future research

“…Furthermore, this tree shrew experiment revealed an activity-induced decrease in the phosphocreatine-to-creatine ratio, suggesting reduced energy charge of the activated cortex (Sonnay et al, 2017). This would be accompanied by a transient increase of ADP that is also capable of inhibiting pyruvate carboxylase activity (Patel & Tilghman, 1973) There has been a wealth of papers over the past few decades on lactate metabolism and the role(s) of lactate in the brain; e.g., (Bak et al, 2009;Dienel, 2012;Hollnagel et al, 2020;Kann, 2023;Lauritzen et al, 2013;Magistretti & Allaman, 2018;Mangia et al, 2009) TA B L E 1 List of published studies from which metabolic fluxes were derived for use in Figure 2 (fluxes with associated standard deviation in μmol/g/min). These studies were selected for having independently determined V PC , V NT , and TCA cycle rates in neurons (V TCA n ) and astrocytes (V TCA a…”

“…There has been a wealth of papers over the past few decades on lactate metabolism and the role(s) of lactate in the brain; e.g., ( Bak et al, 2009 ; Dienel, 2012 ; Hollnagel et al, 2020 ; Kann, 2023 ; Lauritzen et al, 2013 ; Magistretti & Allaman, 2018 ; Mangia et al, 2009 ), with some 16 000 papers resulting from a search for lactate metabolism AND brain in PubMed. Despite all this investigation, lactate is likely the most controversial and misunderstood brain energy substrate.…”

“…Is it important? Well, it can happen, but in the grand scheme of things, no, it is not that important, as lactate is just as likely to efflux from neurons and is not a substrate that can maintain high level neuronal function ( Bak et al, 2006 , 2009 ; Kann, 2023 ; York et al, 2023 ). Giving it a name (ANLS) has given it an importance, which outstrips its role as one of many reasons that lactate enters or leaves cells and the brain.…”

The controllosphere: The neural origin of cognitive effort.

“…This occurs especially in the medial and lateral prefrontal cortex and parietal cortex (Vaishnavi et al, 2010) and generates lactate, which serves as an alternative source of neural fuel (Barros et al, 2021). Significantly, neuronal fueling by lactate is observed to be necessary for tasks with high cognitive load (Dembitskaya et al, 2022) and could contribute to cognitive fatigue (Kann, 2023). Hence, aerobic glycolysis would be a good target for future research on the source of cognitive effort.…”