Non-Canonical Control of Neuronal Energy Status by the Na+ Pump

Baeza-Lehnert, Felipe; Saab, Aiman S.; Gutiérrez, Robin; Larenas, Valeria; Díaz, Esteban F.; Horn, Melanie; Vargas, Miriam; Hösli, Ladina; Stobart, Jillian; Hirrlinger, Johannes; Weber, Bruno; Barros, L. Felipe

doi:10.1016/j.cmet.2018.11.005

Cited by 98 publications

(117 citation statements)

References 78 publications

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“…In contrast to activity and stimulation patterns that involved global [Na + ] i elevations, spatially restricted local [Na + ] i influx as observed upon brief pressure application of glutamate onto dendrites did not evoke a detectable decrease in [ATP] i . A recent study that failed to observe changes in somatic ATP levels in response to electrical activity and Na + influx concluded that ATP consumption by the NKA is matched by a direct increase in mitochondrial ATP production (Baeza-Lehnert et al 2019). Earlier work by us and other laboratories, together with the results presented here, provides an alternative and/or additional explanation for the lack of changes in neuronal [ATP] levels despite relevant increases in [Na + ] i and the efficient recovery thereof.…”

Section: Relation Between Sodium and Atpmentioning

confidence: 49%

“…A recent study that failed to observe changes in somatic ATP levels in response to electrical activity and Na + influx concluded that ATP consumption by the NKA is matched by a direct increase in mitochondrial ATP production (Baeza‐Lehnert et al . ). Earlier work by us and other laboratories, together with the results presented here, provides an alternative and/or additional explanation for the lack of changes in neuronal [ATP] levels despite relevant increases in [Na + ] i and the efficient recovery thereof.…”

Section: Discussionmentioning

confidence: 97%

“…Combined with a direct stimulation of ATP production (Baeza‐Lehnert et al . ) and with diffusion of ATP itself, diffusion‐driven recovery from activity‐related [Na + ] i transients, which does not require direct local ATP consumption, will spread the metabolic burden from activated neuronal microdomains to neighbouring, unstimulated regions.…”

Section: Discussionmentioning

confidence: 99%

“…To answer these questions and gain more insight into brain metabolism, protein-based, genetically encoded fluorescent indicators are increasingly employed (Tantama et al 2012). Here, we have used the Förster resonance energy transfer (FRET)-based nanosensor ATeam1.03 YEMK (ATeam) (Imamura et al 2009), which has already been successfully employed to analyse ATP dynamics in neurons and astrocytes in cell culture and in brain tissue (Trevisiol et al 2017;Winkler et al 2017;Baeza-Lehnert et al 2019;Lerchundi et al 2019). Using this tool, we studied the relationship between different patterns of activity, Na + transients and [ATP] in somata and dendrites of CA1 pyramidal neurons in mouse hippocampal tissue slices.…”

Section: Introductionmentioning

confidence: 99%

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Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Gerkau

Lerchundi

Nelson

et al. 2019

The Journal of Physiology

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Key points Employing quantitative Na+‐imaging and Förster resonance energy transfer‐based imaging with ATeam1.03YEMK (ATeam), we studied the relation between activity‐induced Na+ influx and intracellular ATP in CA1 pyramidal neurons of the mouse hippocampus. Calibration of ATeam in situ enabled a quantitative estimate of changes in intracellular ATP concentrations. Different paradigms of stimulation that induced global Na+ influx into the entire neuron resulted in decreases in [ATP] in the range of 0.1–0.6 mm in somata and dendrites, while Na+ influx that was locally restricted to parts of dendrites did not evoke a detectable change in dendritic [ATP]. Our data suggest that global Na+ transients require global cellular activation of the Na+/K+‐ATPase resulting in a consumption of ATP that transiently overrides its production. For recovery from locally restricted Na+ influx, ATP production as well as fast intracellular diffusion of ATP and Na+ might prevent a local drop in [ATP]. Abstract Excitatory neuronal activity results in the influx of Na+ through voltage‐ and ligand‐gated channels. Recovery from accompanying increases in intracellular Na+ concentrations ([Na+]i) is mainly mediated by the Na+/K+‐ATPase (NKA) and is one of the major energy‐consuming processes in the brain. Here, we analysed the relation between different patterns of activity‐induced [Na+]i signalling and ATP in mouse hippocampal CA1 pyramidal neurons by Na+ imaging with sodium‐binding benzofurane isophthalate (SBFI) and employing the genetically encoded nanosensor ATeam1.03YEMK (ATeam). In situ calibrations demonstrated a sigmoidal dependence of the ATeam Förster resonance energy transfer ratio on the intracellular ATP concentration ([ATP]i) with an apparent KD of 2.6 mm, indicating its suitability for [ATP]i measurement. Induction of recurrent network activity resulted in global [Na+]i oscillations with amplitudes of ∼10 mm, encompassing somata and dendrites. These were accompanied by a steady decline in [ATP]i by 0.3–0.4 mm in both compartments. Global [Na+]i transients, induced by afferent fibre stimulation or bath application of glutamate, caused delayed, transient decreases in [ATP]i as well. Brief focal glutamate application that evoked transient local Na+ influx into a dendrite, however, did not result in a measurable reduction in [ATP]i. Our results suggest that ATP consumption by the NKA following global [Na+]i transients temporarily overrides its availability, causing a decrease in [ATP]i. Locally restricted Na+ transients, however, do not result in detectable changes in local [ATP]i, suggesting that ATP production, together with rapid intracellular diffusion of both ATP and Na+ from and to unstimulated neighbouring regions, counteracts a local energy shortage under these conditions.

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Section: Relation Between Sodium and Atpmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Gerkau

Lerchundi

Nelson

et al. 2019

The Journal of Physiology

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“…From previous studies in mammalian cells, it has been proposed that glial‐derived lactate can supply the energy requirements for neuronal function. However, it is still a matter of debate whether this mechanism operates in vivo during resting states or during increased neuronal activity (Baeza‐Lehnert et al, ; Barros & Weber, ; Diaz‐Garcia & Yellen, ; Dienel, ). In Drosophila , glial glycolysis is necessary for survival, suggesting that transport of lactate from glial cells fuels neurons (Volkenhoff et al, ).…”

Section: Resultsmentioning

confidence: 99%

Neuronal lactate levels depend on glia‐derived lactate during high brain activity in Drosophila

González-Gutiérrez

Ibacache

Esparza

et al. 2019

Glia

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Lactate/pyruvate transport between glial cells and neurons is thought to play an important role in how brain cells sustain the high‐energy demand that neuronal activity requires. However, the in vivo mechanisms and characteristics that underlie the transport of monocarboxylates are poorly described. Here, we use Drosophila expressing genetically encoded FRET sensors to provide an ex vivo characterization of the transport of monocarboxylates in motor neurons and glial cells from the larval ventral nerve cord. We show that lactate/pyruvate transport in glial cells is coupled to protons and is more efficient than in neurons. Glial cells maintain higher levels of intracellular lactate generating a positive gradient toward neurons. Interestingly, during high neuronal activity, raised lactate in motor neurons is dependent on transfer from glial cells mediated in part by the previously described monocarboxylate transporter Chaski, providing support for in vivo glia‐to‐neuron lactate shuttling during neuronal activity.

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Bidirectional astrocytic GLUT1 activation by elevated extracellular K⁺

Fernández‐Moncada

Robles-Maldonado

Castro

et al. 2020

Glia

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The acute rise in interstitial K+ that accompanies neural activity couples the energy demand of neurons to the metabolism of astrocytes. The effects of elevated K+ on astrocytes include activation of aerobic glycolysis, inhibition of mitochondrial respiration and the release of lactate. Using a genetically encoded FRET glucose sensor and a novel protocol based on 3‐O‐methylglucose trans‐acceleration and numerical simulation of glucose dynamics, we report that extracellular K+ is also a potent and reversible modulator of the astrocytic glucose transporter GLUT1. In cultured mouse astrocytes, the stimulatory effect developed within seconds, engaged both the influx and efflux modes of the transporter, and was detected even at 1 mM incremental K+. The modulation of GLUT1 explains how astrocytes are able to maintain their glucose pool in the face of strong glycolysis stimulation. We propose that the stimulation of GLUT1 by K+ supports the production of lactate by astrocytes and the timely delivery of glucose to active neurons.

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Non-Canonical Control of Neuronal Energy Status by the Na+ Pump

Cited by 98 publications

References 78 publications

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Neuronal lactate levels depend on glia‐derived lactate during high brain activity in Drosophila

Bidirectional astrocytic GLUT1 activation by elevated extracellular K⁺

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Non-Canonical Control of Neuronal Energy Status by the Na+ Pump

Cited by 98 publications

References 78 publications

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Neuronal lactate levels depend on glia‐derived lactate during high brain activity in Drosophila

Bidirectional astrocytic GLUT1 activation by elevated extracellular K+

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Bidirectional astrocytic GLUT1 activation by elevated extracellular K⁺