Lactate in the brain: from metabolic end-product to signalling molecule

Abstract

Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.

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Figure 1: Glucose metabolism in astrocytes and neurons.
Figure 2: Lactate-mediated metabolic coupling and signalling between neurons and astrocytes.
Figure 3: Lactate transfer from astrocytes to neurons modulates the excitability of pyramidal cells.
Figure 4: Lactate transfer from astrocytes to neurons in memory consolidation.

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Acknowledgements

Research in P.J.M.'s laboratory has been supported over the years by the Swiss National Science Foundation, King Abdullah University of Science and Technology (KAUST; Saudi Arabia), the University of Lausanne (UNIL; Switzerland), École Polytechnique Fédérale de Lausanne (EPFL; Switzerland), Centre Hospitalier Universitaire Vaudois (CHUV; Switzerland), the National Centre for Competence in Research (NCCR) Synapsy and the Préfargier Foundation. The authors thank H. Fiumelli and F. Barros for comments on the manuscript.

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P.J.M. wrote the manuscript. P.J.M. and I.A. researched data for the article, made substantial contributions to the discussion of content and reviewed and edited the manuscript before submission.

Correspondence to Pierre J. Magistretti.

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Glossary

Pyruvate dehydrogenase

(PDH). The first component enzyme of the pyruvate dehydrogenase complex; it converts pyruvate into acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle for cellular respiration.

Glycolytic flux

The rate at which glucose and its metabolites proceed through the glycolytic pathway.

Flux analysis

A technique used to examine production and consumption rates of metabolites. It determines the transfer of moieties containing isotopic tracers from one metabolite into another using stoichiometric models of metabolism and mass spectrometry methods.

Mitochondrial respiratory chain (MRC) complexes

Complexes that operate the transfer of electrons from donors to acceptors via redox mechanisms, creating an electrochemical proton gradient that drives the synthesis of ATP.

Complex I

The first step in the mitrochondrial respiratory chain; it removes two electrons from NADH and operates their transfer to ubiquinone.

Transacceleration

A property of monocarboxylate transporters whereby the presence of extracellular monocarboxylates (such as pyruvate) stimulates transporter efflux of the substrate (for example, lactate).

Warburg effect

Also called aerobic glycolysis. The metabolic pathway of glucose that results in the production of lactate in the presence of physiological concentrations of oxygen.

Fast glucose transport

Facilitated transmembrane transport of glucose via specific transporters.

Energy charge

An index that measures the energy status of cells. It is related to ATP, ADP and AMP concentrations.

Memory consolidation

A category of processes whereby a brain converts short-term memories into long-term memories (that is, stabilizing a memory trace after its initial acquisition).

Glycogen phosphorylase

The enzyme that catalyses the rate-limiting step in glycogenolysis.

Inhibitory avoidance

A behavioural task that is commonly used to investigate learning and memory processes in rodents and that is based on contextual fear conditioning.

Nucleus solitary tract

A major sensory nucleus in the dorsal medulla that receives cardiovascular, visceral, respiratory, gustatory and orotactile information.

Euglycaemia

Physiological concentration of glucose in the blood.

Ependymal cells

A glial cell type that lines the spinal cord and the ventricular system of the brain and that is involved in the creation, secretion and circulation of cerebrospinal fluid.

Subfornical organ

One of the highly vascularized circumventricular organs of the brain localized on the ventral surface of the fornix. It does not possess a blood–brain barrier.

Macrophage polarization

The process by which macrophages express different functional programmes in response to microenvironmental signals.

Carotid body

A chemosensory organ at the carotid artery bifurcation that is the major sensor of blood oxygen in mammals.

Minute ventilation

The volume of gas inhaled or exhaled by the lungs per minute.

Excitotoxicity

The pathological process by which neurons are damaged or killed by excessive stimulation by glutamate or other excitatory neurotransmitters.

Middle cerebral artery occlusion

An experimental model of stroke based on focal cerebral ischaemia induced by permanent or transient occlusion of the middle cerebral artery in mice or rats.

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Magistretti, P., Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19, 235–249 (2018). https://doi.org/10.1038/nrn.2018.19

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