Adenosine signalling to astrocytes coordinates brain metabolism and function

Shefeeq M. Theparambil (), Olga Kopach, Alice Braga, Shereen Nizari, Patrick S. Hosford, Virag Sagi-Kiss, Anna Hadjihambi, Christos Konstantinou, Noemi Esteras, Ana Gutierrez Del Arroyo, Gareth L. Ackland, Anja G. Teschemacher, Nicholas Dale, Tobias Eckle, Petros Andrikopoulos, Dmitri A. Rusakov, Sergey Kasparov and Alexander V. Gourine ()
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Shefeeq M. Theparambil: University College London
Olga Kopach: University College London
Alice Braga: University College London
Shereen Nizari: University College London
Patrick S. Hosford: University College London
Virag Sagi-Kiss: Imperial College London
Anna Hadjihambi: King’s College London
Christos Konstantinou: King’s College London
Noemi Esteras: University College London
Ana Gutierrez Del Arroyo: Queen Mary University of London
Gareth L. Ackland: Queen Mary University of London
Anja G. Teschemacher: University of Bristol
Nicholas Dale: University of Warwick
Tobias Eckle: University of Colorado Anschutz Medical Campus
Petros Andrikopoulos: Imperial College London
Dmitri A. Rusakov: University College London
Sergey Kasparov: University of Bristol
Alexander V. Gourine: University College London

Nature, 2024, vol. 632, issue 8023, 139-146

Abstract: Abstract Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood5,6. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07611-w

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