Adenosine signalling to astrocytes coordinates brain metabolism and function

• 成果类型: Article
• 署名作者: Theparambil, Shefeeq M.; Kopach, Olga; Braga, Alice; Nizari, Shereen; Hosford, Patrick S.; Sagi-Kiss, Virag; Hadjihambi, Anna; Konstantinou, Christos; Esteras, Noemi; Del Arroyo, Ana Gutierrez; Ackland, Gareth L.; Teschemacher, Anja G.; Dale, Nicholas; Eckle, Tobias; Andrikopoulos, Petros; Rusakov, Dmitri A.; Kasparov, Sergey; Gourine, Alexander V.
• 署名单位: University of London; University College London; Lancaster University; University of London; University College London; Imperial College London; University of London; University College London; King's College London; University of London; King's College London; University of London; Queen Mary University London; University of Bristol; University of Warwick; University of Colorado System; University of Colorado Anschutz Medical Campus; Imperial College London
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5456
• DOI: 10.1038/s41586-024-07611-w
• 发表日期: 2024-08-01
• 关键词: long-term potentiation; release; lactate; glycolysis; cell; atp; mediator; h-1-nmr; serine; memory

摘要

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. This study explores how adenosine A2B receptors can act as astrocytic sensors of brain metabolic activity and how cAMP signalling in astrocytes may support core brain functions such as sleep and memory.