In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons

Mächler, Philipp; Wyss, Matthias T.; Elsayed, Maha; Stobart, Jillian; Gutiérrez, Robin; Faber-Castell, Alexandra von; Kaelin, Vincens; Zuend, Marc; Martín, Alejandro San; Romero-Gómez, Ignacio; Baeza-Lehnert, Felipe; Lengacher, Sylvain; Schneider, Bernard L.; Aebischer, Patrick; Magistretti, Pierre J.; Barros, L. Felipe; Weber, Bruno

doi:10.1016/j.cmet.2015.10.010

Cited by 437 publications

(389 citation statements)

References 71 publications

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“…The GCaMP6s gene from pGP-CMV-GCaMP6s (a gift from Douglas Kim; Addgene plasmid #40753 ) was cloned into a plasmid backbone containing AAV2 inverted terminal repeats, a short GFAP promoter (Gfa-ABC1D or sGFAP (Lee et al 2008)), a β-globin intron, and poly adenylation signal (Mächler et al 2016). This plasmid was packaged into adeno-associated virus (AAV) serotype 9 (AAV9-sGFAP-GCaMP6s) by the University of North Carolina Vector Core.…”

Section: Cloning and Virus Productionmentioning

confidence: 99%

Long-term In Vivo Calcium Imaging of Astrocytes Reveals Distinct Cellular Compartment Responses to Sensory Stimulation

et al. 2016

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Localized, heterogeneous calcium transients occur throughout astrocytes, but the characteristics and long-term stability of these signals, particularly in response to sensory stimulation, remain unknown. Here, we used a genetically encoded calcium indicator and an activity-based image analysis scheme to monitor astrocyte calcium activity in vivo. We found that different subcellular compartments (processes, somata, and endfeet) displayed distinct signaling characteristics. Closer examination of individual signals showed that sensory stimulation elevated the number of specific types of calcium peaks within astrocyte processes and somata, in a cortical layer-dependent manner, and that the signals became more synchronous upon sensory stimulation. Although mice genetically lacking astrocytic IP3R-dependent calcium signaling (Ip3r2−/−) had fewer signal peaks, the response to sensory stimulation was sustained, suggesting other calcium pathways are also involved. Long-term imaging of astrocyte populations revealed that all compartments reliably responded to stimulation over several months, but that the location of the response within processes may vary. These previously unknown characteristics of subcellular astrocyte calcium signals provide new insights into how astrocytes may encode local neuronal circuit activity. AbstractLocalized, heterogeneous calcium transients occur throughout astrocytes, but the characteristics and

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Section: Cloning and Virus Productionmentioning

confidence: 99%

Long-term In Vivo Calcium Imaging of Astrocytes Reveals Distinct Cellular Compartment Responses to Sensory Stimulation

et al. 2016

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“…Astrocytic glycogen is broken down through glycogenolysis/glycolysis to produce lactate as a neuronal energy substrate transported by monocarboxylate transporters (MCTs) (2). Indeed, brain glycogen decreases during memory tasks (3) and in some physiologically exhaustive conditions such as sleep deprivation (4) and hypoglycemia (5).…”

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confidence: 99%

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Matsui

Omuro

Liu

et al. 2017

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

120

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Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remains less clear. Because muscle glycogen fuels exercising muscles, we hypothesized that astrocytic glycogen plays an energetic role in the prolonged-exercising brain to maintain endurance capacity through lactate transport. To test this hypothesis, we used a rat model of exhaustive exercise and capillary electrophoresismass spectrometry-based metabolomics to observe comprehensive energetics of the brain (cortex and hippocampus) and muscle (plantaris). At exhaustion, muscle glycogen was depleted but brain glycogen was only decreased. The levels of MCT2, which takes up lactate in neurons, increased in the brain, as did muscle MCTs. Metabolomics revealed that brain, but not muscle, ATP was maintained with lactate and other glycogenolytic/glycolytic sources. Intracerebroventricular injection of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol did not affect peripheral glycemic conditions but suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An MCT2 inhibitor, α-cyano-4-hydroxycinnamate, triggered a similar response that resulted in lower endurance capacity. These findings provide direct evidence for the energetic role of astrocytic glycogen-derived lactate in the exhaustive-exercising brain, implicating the significance of brain glycogen level in endurance capacity. Glycogen-maintained ATP in the brain is a possible defense mechanism for neurons in the exhausted brain.brain glycogen | lactate transport | ATP | endurance capacity | metabolomics G lucose derived from blood is the primary energy source for generating ATP in the brain, but an important energy reserve is brain glycogen synthesized from glucose in astrocytes (1). Astrocytic glycogen is broken down through glycogenolysis/glycolysis to produce lactate as a neuronal energy substrate transported by monocarboxylate transporters (MCTs) (2). Indeed, brain glycogen decreases during memory tasks (3) and in some physiologically exhaustive conditions such as sleep deprivation (4) and hypoglycemia (5). The genetic/pharmacologic inhibitions of glycogenolysis and/or lactate transport impair neuronal survival under severe hypoglycemia, as well as axon transmission and hippocampus-related memory formation (6-8). Therefore, astrocytic glycogen-derived lactate is a critical energy source for meeting brain energy demands for neuronal functions and/or survival.Although less than for exercising muscles, physical exercise activates brain neurons and increases brain energy demand (9). Blood glucose and lactate contribute to brain energetics during moderate or intense exercise (10, 11). Muscle glycogen is an important energy for maintaining muscle contraction during endurance ex...

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“…Acting in synergy with NH 4 ϩ , which also inhibits mitochondrial pyruvate consumption (18), endothelial NO is expected to contribute to the standing astrocytic lactate reservoir (17,57,58) that is acutely released to the interstitium "on demand" via a K ϩ -activated lactate channel (17). Lactate is a metabolic fuel and also an intercellular signal that modulates multiple functions in brain tissue, from vascular tone to memory processing (59 -61), and therefore the effect of NO on astrocytic mitochondria may be understood as a modulator of these functions.…”

Section: Possible Roles Of Cytochrome Oxidase Inhibition By No Lactamentioning

confidence: 99%

Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism

Martín

Arce-Molina

Galaz

et al. 2017

Journal of Biological Chemistry

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Nitric oxide (NO) is an intercellular messenger involved in multiple bodily functions. Prolonged NO exposure irreversibly inhibits respiration by covalent modification of mitochondrial cytochrome oxidase, a phenomenon of pathological relevance. However, the speed and potency of NO's metabolic effects at physiological concentrations are incompletely characterized. To this end, we set out to investigate the metabolic effects of NO in cultured astrocytes from mice by taking advantage of the high spatiotemporal resolution afforded by genetically encoded Förster resonance energy transfer (FRET) nanosensors. NO exposure resulted in immediate and reversible intracellular glucose depletion and lactate accumulation. Consistent with cytochrome oxidase involvement, the glycolytic effect was enhanced at a low oxygen level and became irreversible at a high NO concentration or after prolonged exposure. Measurements of both glycolytic rate and mitochondrial pyruvate consumption revealed significant effects even at nanomolar NO concentrations. We conclude that NO can modulate astrocytic energy metabolism in the short term, reversibly, and at concentrations known to be released by endothelial cells under physiological conditions. These findings suggest that NO modulates the size of the astrocytic lactate reservoir involved in neuronal fueling and signaling.In brain tissue and retina, NO contributes to both vasodilation and vasoconstriction (1, 2). The vasoactive effects of NO are mediated by the enzymes guanylate cyclase, cytochrome P450 epoxygenase, and -hydroxylase, which sense different NO concentrations. Guanylate cyclase is stimulated in the picomolar to low nanomolar range, whereas cytochrome P450 enzymes are inhibited at tens to hundreds of nanomolar NO (1, 3). However, there is more to NO than vasodilation. Endothelial cells express both endothelial NO synthase (eNOS) 3 and inducible NO synthase (iNOS) (4) resulting in NO production strong enough to sustain up to 70 nM extracellular NO in response to shear stress (5), to reach cells millimeters away in bicameral cultures (6), or to permeate across layers of astrocytes and myelin toward axons in vivo (7). A fourth well characterized molecular target of NO is mitochondrial cytochrome oxidase (EC 1.9.3.1), whose sensitivity to NO is similar to that of cytochrome P450 (8, 9). As inhibition of cytochrome oxidase reduces local oxygen consumption, endothelial NO has been proposed to extend the effective zone of oxygenation away from the vessel (10). A role for NO-dependent mitochondrial inhibition in brain tissue was suggested upon the observation that NO inhibits astrocytic respiration, resulting in stimulated glycolysis and lactate production (11, 12). Conceivably, inhibition of cytochrome oxidase may not only play a tonic distributive role but may also participate in activity-dependent neurometabolic coupling (13). However, there are aspects that need further exploring, notably the speed and potency of the metabolic effects in the face of actual NO concentrations found under...

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In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons

Cited by 437 publications

References 71 publications

Long-term In Vivo Calcium Imaging of Astrocytes Reveals Distinct Cellular Compartment Responses to Sensory Stimulation

Long-term In Vivo Calcium Imaging of Astrocytes Reveals Distinct Cellular Compartment Responses to Sensory Stimulation

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism

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