Is lactate a volume transmitter of metabolic states of the brain?

Bergersen, Linda Hildegard; Gjedde, Albert

doi:10.3389/fnene.2012.00005

Cited by 100 publications

(92 citation statements)

References 79 publications

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“…L-lactate transport into cells through MCTs and further metabolism seems an obligatory route to affect cell energetics and functions, although recent evidence suggests that it could also affect cell responsiveness through its binding to a specific G-coupled cell surface receptor, GPR81 (20). Consistent with a transport-mediated effect of L-lactate, IEG expression was blocked in the presence of the MCT inhibitor UK5099.…”

Section: Discussionsupporting

confidence: 53%

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Yang

Ruchti

Petit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

402

373

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L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.brain energy metabolism | learning and memory | astrocyte-neuron interaction | astrocyte-neuron lactate shuttle T he transfer of L-lactate from astrocytes to neurons was recently shown to be necessary for the establishment of longterm memory (LTM) in an inhibitory avoidance (IA) paradigm and for the maintenance of in vivo long-term potentiation (LTP) in the rodent hippocampus (1). This key role of L-lactate in neuronal plasticity mechanisms was demonstrated in experiments in which specific pharmacological and gene expression down-regulation interventions were implemented to prevent the production of L-lactate from glycogen-which is exclusively localized in astrocytes-and its release from these cells in the hippocampus during behavioral training (1). Such interventions completely prevented the establishment of LTM and their effect was fully reversed by the intrahippocampal administration of L-lactate during the training session. The fact that glucose at equicaloric concentrations only marginally mimicked the rescuing effect of L-lactate was taken as an unexpected indication that the primary mechanism of action of L-lactate on plasticity mechanisms was independent of its ability to act as an energy substrate. A role of L-lactate in memory processes was also recently shown in other behavioral paradigms (2, 3). We therefore set out to investigate the molecular mechanisms at the basis of the function of L-lactate on neuronal plasticity.Molecular mechanisms underlying both LTM and long-term plasticity include the induction of expression of a group of immediate early genes (IEGs) such as early growth response 1 (Zif268 or Egr1), CCAAT/enhancer binding protein (C/EBP), and proto-oncogene c-Fos (c-Fos) as well as activity-regulated cytoskeletal-associated protein (Arc or Arg3.1) as a direct effector protein at the synapse, which all participate to different physiological processes associated with neuronal p...

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Section: Discussionsupporting

confidence: 53%

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Yang

Ruchti

Petit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

402

373

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“…A significant mediator, it can impact the metabolism of cells far from their site of origin by regulating the formation of cAMP via the GPR81 lactate receptor, and by influencing the ratio of NADH / NAD+. Both processes are associated with the regulation of energy in the brain and indirectly, blood flow 16 . Lactate also functions as a "critical buffer" which enables an increased rate of glycolysis to meet increased energy demands due to stress.…”

Section: Discussionmentioning

confidence: 99%

Lactate as an early predictor of psychomotor development in neonates with asphyxia receiving therapeutic hypothermia

Polackova¹,

Šalounová²,

Kantor³

2018

BIOMED PAP

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Aims. This prospective study aimed to evaluate the relationship between persistently elevated lactate values in the arterial blood of newborns with grade II and III hypoxic ischemic encephalopathy (treated with therapeutic hypothermia) and psychomotor development at 24 months. Methods. 51 neonates of gestational age from 36 to 41 weeks receiving therapeutic hypothermia for moderate to severe hypoxic ischaemic encephalopathy had arterial blood lactate levels regularly analysed. At 24 months the infants' psychomotor development was evaluated and they were divided into two groups -those where the outcome was favourable (i.e. normal psychomotor development) and adverse (severe motor or sensory impairment or death). The lactate dynamics over time were retrospectively evaluated from the data collected, with the normal upper limit set at 4 mmol/L. Results. Of the 51 affected neonates, 7 died over the course of the study. 34 of the remaining 44 infants demonstrated normal psychomotor findings at 2 years old, with adverse findings in 10 cases. Although both groups experienced significant reductions in lactate over time, there were statistically significant differences between them regarding currently measured lactate levels. Conclusion.Absolute lactate values and their development over time can be a used as an auxiliary factor in making early estimates of the long-term outcome for newborns with neonatal asphyxia being treated with therapeutic hypothermia.

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“…97 The existence of a lactate receptor in brain 4 bolsters the role of lactate as a 'volume transmitter', a role suggested in a perspectives article in 2012. 3 The distribution of MCTs among brain cells (Figure 1) sets the scene for this volume transmitter action of lactate: through the equilibrating, facilitatory transport mediated by the MCTs, lactate will diffuse down its concentration gradient from sites of net production to reach lactate receptor sites via intracellular and extracellular compartments. The entry of lactate into brain tissue at the BBB to act on HCAR1 on brain cells is related to the volume transmission concept.…”

Section: Lactate-a Volume Transmittermentioning

confidence: 99%

“…The equilibrating action of MCTs also provides the basis for lactate acting as a volume transmitter that can mediate metabolic signals through the nervous tissue. 3 The latter concept was underpinned by the demonstration that lactate can bind to the lactate receptor GPR81 (hydroxycarboxylic acid receptor, HCAR1), on brain cells and cerebral blood vessels, resulting in inhibition of adenylyl cyclase. 4 The localization and function of HCAR1 and the three MCTs (MCT1, MCT2, and MCT4) expressed in brain will be the focus of this review ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction

Bergersen

2014

J Cereb Blood Flow Metab

199

166

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Lactate acts as a 'buffer' between glycolysis and oxidative metabolism. In addition to being exchanged as a fuel by the monocarboxylate transporters (MCTs) between cells and tissues with different glycolytic and oxidative rates, lactate may be a 'volume transmitter' of brain signals. According to some, lactate is a preferred fuel for brain metabolism. Immediately after brain activation, the rate of glycolysis exceeds oxidation, leading to net production of lactate. At physical rest, there is a net efflux of lactate from the brain into the blood stream. But when blood lactate levels rise, such as in physical exercise, there is net influx of lactate from blood to brain, where the lactate is used for energy production and myelin formation. Lactate binds to the lactate receptor GPR81 aka hydroxycarboxylic acid receptor (HCAR1) on brain cells and cerebral blood vessels, and regulates the levels of cAMP. The localization and function of HCAR1 and the three MCTs (MCT1, MCT2, and MCT4) expressed in brain constitute the focus of this review. They are possible targets for new therapeutic drugs and interventions. The author proposes that lactate actions in the brain through MCTs and the lactate receptor underlie part of the favorable effects on the brain resulting from physical exercise.

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Is lactate a volume transmitter of metabolic states of the brain?

Cited by 100 publications

References 79 publications

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Lactate as an early predictor of psychomotor development in neonates with asphyxia receiving therapeutic hypothermia

Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction

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