CrossTalk opposing view: lack of evidence supporting an astrocyte‐to‐neuron lactate shuttle coupling neuronal activity to glucose utilisation in the brain

Abstract

In 1993, Dringen et al. concluded that 'glycogen in astrocytes can be considered as a store for lactate rather than for glucose' , and suggested that lactate derived from the breakdown of glycogen in astrocytes may serve the energetic needs of neighbouring cells. The following year, Pellerin and Magistretti (1994) published their now famed astrocyte-to-neuron lactate shuttle hypothesis in which the transfer of lactate from astrocytes to neurons, in this case derived from extracellular glucose rather than glycogen, is coupled to uptake of neurotransmitter glutamate (i.e. neuronal activity). According to this hypothesis, glycolysis and lactate production are astrocytic phenomena while oxidative metabolism of lactate takes place in neurons. The astrocyte-to-neuron lactate shuttle hypothesis as proposed by Pellerin and Magistretti (1994) has gained widespread acceptance, and its popularity is not surprising due to its conceptually simple and compelling idea of an activity-based coupling between neuronal synaptic activity and astrocyte metabolism. We will argue that the biochemical and physiological Lasse K. Bak is an associate professor at the Department of Drug Design and Pharmacology at University of Copenhagen, Denmark. His research focuses on understanding compartmentalised cAMP and Ca 2+ signals, and signalling-metabolism coupling in brain cells in search of novel drug targets for brain pathologies such as dementias and epilepsy. Anne B. Walls is an associate professor at the Department of Drug Design and Pharmacology at University of Copenhagen, Denmark. Her research focuses on understanding energy and amino acid metabolism in brain cells and its coupling to cerebral activity in pathologies such as hepatic encephalopathy and epilepsy.evidence for the existence of a unidirectional flow of lactate from astrocytes to neurons, as proposed, is lacking. However, before we get to that, let us briefly explore why this subject is even interesting to physiologists. Why is this issue worth a CrossTalk debate?First of all, the extensive acceptance of the astrocyte-to-neuron lactate shutte means that many researchers use this hypothesis as a master template on which they interpret their data, thus ignoring alternative explanations and hence creating a bias in the literature. Besides this, and of course the pure scientific desire to know how the brain operates, the cellular site of glucose metabolism in the brain is important for interpreting fluorodeoxyglucose (FDG) positron emission tomography (PET) results, a method extensively used for both research and diagnostic purposes. In the following, we will focus on two key issues that we believe severely contest the existence of a lactate shuttle from astrocytes to neurons, as proposed: (1) neurons express glucose transporters and metabolise glucose in an activity-dependent manner; and (2) the distinct cellular isoform expression of lactate transporters and lactate dehydrogenase, the enzyme forming lactate from pyruvate, cannot be employed as an argument for a directional flow...

NBCe1 mediates the regulation of the NADH/NAD+redox state in cortical astrocytes by neuronal signals

“…This increase might diminish the redox gradient between astrocytes and neurons, thereby abolishing the driving force of lactate transfer during neuronal activity. Recent evidence put forward the hypothesis of lactate release from neurons in the dentate gyrus during activity (Diaz-Garcia et al, 2017), but certainly further work is required to elaborate a complete view on metabolic coupling in different brain areas, with different types of neurons, with metabolically heterogeneous astrocytes, under different states of activity, and most likely even at different subcellular domains (Bak & Walls, 2018;Barros & Weber, 2018;Oheim et al, 2018). While to finally solve this issue, quantification of the NADH/NAD + redox ratio (and other metabolites) in astrocytes and neurons in vivo in the awake animal during rest and activity would be desirable, our data provide strong evidence that the difference in redox state in astrocytes and neurons is maintained even during periods of strong neuronal activity.…”

FRET‐based imaging of intracellular ATP in organotypic brain slices

“…While there is a wealth of experimental evidence supporting this so‐called astrocyte‐neuron lactate shuttle, there is an ongoing debate about its relevance (Bak & Walls, ; Barros & Weber, ), indicating that many aspects of neuron‐glia interaction and metabolic relationships between astrocytes and neurons are still not understood in detail. This is partly due to the lack of appropriate tools in the past, circumventing a dynamic determination of activity‐related changes in energy metabolites in brain tissue with (sub‐) cellular resolution (Barros et al, ).…”

Aspects of astrocytic cAMP signaling with an emphasis on the putative power of compartmentalized signals in health and disease

“…In the model proposed by Choi et al, the elevation in extracellular K + produced by neuronal activity causes an increase in astrocytic HCO 3 − levels by uptake of K + and downstream activity of the Na + / HCO 3 − co‐transporter. This increase in HCO 3 − was suggested to activate sAC and the subsequent cAMP response to lead to degradation of glycogen providing lactate to support the high energy demanding synaptic activity (for recent reviews on the role of lactate shuttling from astrocytes to neurons, please see Bak & Walls, ; Bak & Walls, ; Barros & Weber, ; Barros & Weber, ; Diaz‐Garcia & Yellen, ). One potentially severe caveat in the study by Choi et al () is that they employed KH7, a selective inhibitor of sAC, in their key experiments.…”