Adenosine signalling to astrocytes coordinates brain metabolism and function

doi:10.1038/s41586-024-07611-w

. 2024 Jul 3.

doi: 10.1038/s41586-024-07611-w. Online ahead of print.

Adenosine signalling to astrocytes coordinates brain metabolism and function

Shefeeq M Theparambil^{1

2}, Olga Kopach³, Alice Braga⁴, Shereen Nizari⁴, Patrick S Hosford⁴, Virag Sagi-Kiss⁵, Anna Hadjihambi⁶, Christos Konstantinou⁶, Noemi Esteras³, Ana Gutierrez Del Arroyo⁷, Gareth L Ackland⁷, Anja G Teschemacher⁸, Nicholas Dale⁹, Tobias Eckle¹⁰, Petros Andrikopoulos¹¹, Dmitri A Rusakov³, Sergey Kasparov⁸, Alexander V Gourine¹²

Affiliations

¹ Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK. s.theparambil@ucl.ac.uk.
² Department of Biomedical and Life Sciences, Lancaster University, Lancaster, UK. s.theparambil@ucl.ac.uk.
³ Institute of Neurology, University College London, London, UK.
⁴ Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK.
⁵ Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
⁶ The Roger Williams Institute of Hepatology, Foundation for Liver Research & Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁷ Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK.
⁸ Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, UK.
⁹ School of Life Sciences, University of Warwick, Coventry, UK.
¹⁰ Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹ Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
¹² Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK. a.gourine@ucl.ac.uk.

PMID: 38961289
DOI: 10.1038/s41586-024-07611-w

Adenosine signalling to astrocytes coordinates brain metabolism and function

Shefeeq M Theparambil et al. Nature. 2024.

. 2024 Jul 3.

doi: 10.1038/s41586-024-07611-w. Online ahead of print.

Authors

Affiliations

¹ Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK. s.theparambil@ucl.ac.uk.
² Department of Biomedical and Life Sciences, Lancaster University, Lancaster, UK. s.theparambil@ucl.ac.uk.
³ Institute of Neurology, University College London, London, UK.
⁴ Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK.
⁵ Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
⁶ The Roger Williams Institute of Hepatology, Foundation for Liver Research & Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁷ Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK.
⁸ Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, UK.
⁹ School of Life Sciences, University of Warwick, Coventry, UK.
¹⁰ Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹ Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
¹² Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK. a.gourine@ucl.ac.uk.

PMID: 38961289
DOI: 10.1038/s41586-024-07611-w

Abstract

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply^1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism^3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood^5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3',5'-monophosphate-protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.

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References

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1. Attwell, D. & Laughlin, S. B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001). - PubMed - DOI
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1. Suzuki, A. et al. Astrocyte–neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011). - PubMed - PMC - DOI
1. Magistretti, P. J. & Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249 (2018). - PubMed - DOI

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[1] Fox, P. T., Raichle, M. E., Mintun, M. A. & Dence, C. Nonoxidative glucose consumption during focal physiologic neural activity. Science 241, 462–464 (1988). - PubMed - DOI

[2] Fox, P. T., Raichle, M. E., Mintun, M. A. & Dence, C. Nonoxidative glucose consumption during focal physiologic neural activity. Science 241, 462–464 (1988). - PubMed - DOI

[3] Attwell, D. & Laughlin, S. B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001). - PubMed - DOI

[4] Attwell, D. & Laughlin, S. B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001). - PubMed - DOI

[5] Rouach, N., Koulakoff, A., Abudara, V., Willecke, K. & Giaume, C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555 (2008). - PubMed - DOI

[6] Rouach, N., Koulakoff, A., Abudara, V., Willecke, K. & Giaume, C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555 (2008). - PubMed - DOI

[7] Suzuki, A. et al. Astrocyte–neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011). - PubMed - PMC - DOI

[8] Suzuki, A. et al. Astrocyte–neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011). - PubMed - PMC - DOI

[9] Magistretti, P. J. & Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249 (2018). - PubMed - DOI

[10] Magistretti, P. J. & Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249 (2018). - PubMed - DOI

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Adenosine signalling to astrocytes coordinates brain metabolism and function

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Adenosine signalling to astrocytes coordinates brain metabolism and function

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