Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

Mosienko, Valentina; Rasooli-Nejad, Ali; Kishi, Kasumi; Both, Matt De; Jane, David E.; Huentelman, Matthew J.; Kasparov, Sergey; Teschemacher, Anja G.

doi:10.3390/neuroglia1020025

Cited by 18 publications

(19 citation statements)

References 53 publications

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“…Some reports have proposed the existence of other putative lactate receptors, with Gs activity instead of the HCAR1 Gi activity (Tang et al, 2014;Vardjan et al, 2018;D' Adamo et al, 2021). However, the evidence and characterization of these receptors still remain elusive (Mosienko et al, 2018). Others have proposed the interaction of the HCAR1 Giβγ moiety with other GPCRs, and the activation of ERK1/2, PI3K, and Akt pathways following HCAR1 stimulation (Li et al, 2014;de Castro Abrantes et al, 2019;Herrera-López et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Hydroxycarboxylic Acid Receptor 1 and Neuroprotection in a Mouse Model of Cerebral Ischemia-Reperfusion

et al. 2021

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Lactate is an intriguing molecule with emerging physiological roles in the brain. It has beneficial effects in animal models of acute brain injuries and traumatic brain injury or subarachnoid hemorrhage patients. However, the mechanism by which lactate provides protection is unclear. While there is evidence of a metabolic effect of lactate providing energy to deprived neurons, it can also activate the hydroxycarboxylic acid receptor 1 (HCAR1), a Gi-coupled protein receptor that modulates neuronal firing rates. After cerebral hypoxia-ischemia, endogenously produced brain lactate is largely increased, and the exogenous administration of more lactate can decrease lesion size and ameliorate the neurological outcome. To test whether HCAR1 plays a role in lactate-induced neuroprotection, we injected the agonists 3-chloro-5-hydroxybenzoic acid and 3,5-dihydroxybenzoic acid into mice subjected to 30-min middle cerebral artery occlusion. The in vivo administration of HCAR1 agonists at reperfusion did not appear to exert any relevant protective effect as seen with lactate administration. Our results suggest that the protective effects of lactate after hypoxia-ischemia come rather from the metabolic effects of lactate than its signaling through HCAR1.

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Section: Discussionmentioning

confidence: 99%

Hydroxycarboxylic Acid Receptor 1 and Neuroprotection in a Mouse Model of Cerebral Ischemia-Reperfusion

et al. 2021

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“…. Astrocyte-derived L-lactate (lactate), in particular, has gained increasing attention due to its dual role as a metabolic and signaling molecule in the brain (Barros & Weber, 2018;Karagiannis et al, 2015;Magistretti & Allaman, 2018;Marina et al, 2018Marina et al, , 2020Mosienko et al, 2018;Mosienko, Teschemacher, & Kasparov, 2015).…”

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confidence: 99%

Reducing l‐lactate release from hippocampal astrocytes by intracellular oxidation increases novelty induced activity in mice

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et al. 2021

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Astrocytes are in control of metabolic homeostasis in the brain and support and modulate neuronal function in various ways. Astrocyte‐derived l‐lactate (lactate) is thought to play a dual role as a metabolic and a signaling molecule in inter‐cellular communication. The biological significance of lactate release from astrocytes is poorly understood, largely because the tools to manipulate lactate levels in vivo are limited. We therefore developed new viral vectors for astrocyte‐specific expression of a mammalianized version of lactate oxidase (LOx) from Aerococcus viridans. LOx expression in astrocytes in vitro reduced their intracellular lactate levels as well as the release of lactate to the extracellular space. Selective expression of LOx in astrocytes of the dorsal hippocampus in mice resulted in increased locomotor activity in response to novel stimuli. Our findings suggest that a localized decreased intracellular lactate pool in hippocampal astrocytes could contribute to greater responsiveness to environmental novelty. We expect that use of this molecular tool to chronically limit astrocytic lactate release will significantly facilitate future studies into the roles and mechanisms of intercellular lactate communication in the brain.

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“…We next asked whether the cAMP signalling involving the putative l -lactate receptor mechanisms [ 41 ] is affected in Gdi1 WT and Gdi1 KO astrocytes. For this, extracellular l -lactate (20 mM; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The identity of l -lactate receptors in the brain has been considered in primary cortical neurons, where extracellular l -lactate modulates neuronal activity via a receptor-mediated process [ 49 ], recently described as the HCAR 1 (GPR81) receptor [ 50 ], the canonical l -lactate receptor, originally discovered in adipocytes [ 51 ]. However, this receptor is unlikely present in the locus coeruleus neuronal somata [ 40 ], where a multitude of l -lactate receptors may play a role [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse

et al. 2021

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Objectives GDI1 gene encodes for αGDI, a protein controlling the cycling of small GTPases, reputed to orchestrate vesicle trafficking. Mutations in human GDI1 are responsible for intellectual disability (ID). In mice with ablated Gdi1 , a model of ID, impaired working and associative short-term memory was recorded. This cognitive phenotype worsens if the deletion of αGDI expression is restricted to neurons. However, whether astrocytes, key homeostasis providing neuroglial cells, supporting neurons via aerobic glycolysis, contribute to this cognitive impairment is unclear. Methods We carried out proteomic analysis and monitored [ 18 F]-fluoro-2-deoxy- d -glucose uptake into brain slices of Gdi1 knockout and wild type control mice. d -Glucose utilization at single astrocyte level was measured by the Förster Resonance Energy Transfer (FRET)-based measurements of cytosolic cyclic AMP, d -glucose and L-lactate, evoked by agonists selective for noradrenaline and L-lactate receptors. To test the role of astrocyte-resident processes in disease phenotype, we generated an inducible Gdi1 knockout mouse carrying the Gdi1 deletion only in adult astrocytes and conducted behavioural tests. Results Proteomic analysis revealed significant changes in astrocyte-resident glycolytic enzymes. Imaging [ 18 F]-fluoro-2-deoxy- d -glucose revealed an increased d -glucose uptake in Gdi1 knockout tissue versus wild type control mice, consistent with the facilitated d -glucose uptake determined by FRET measurements. In mice with Gdi1 deletion restricted to astrocytes, a selective and significant impairment in working memory was recorded, which was rescued by inhibiting glycolysis by 2-deoxy- d -glucose injection. Conclusions These results reveal a new astrocyte-based mechanism in neurodevelopmental disorders and open a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice.

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Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

Cited by 18 publications

References 53 publications

Hydroxycarboxylic Acid Receptor 1 and Neuroprotection in a Mouse Model of Cerebral Ischemia-Reperfusion

Hydroxycarboxylic Acid Receptor 1 and Neuroprotection in a Mouse Model of Cerebral Ischemia-Reperfusion

Reducing l‐lactate release from hippocampal astrocytes by intracellular oxidation increases novelty induced activity in mice

Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse

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