英国伦敦大学学院Alexander V. Gourine等研究人员合作发现，腺苷信号传递至星形胶质细胞来协调大脑代谢与功能。2024年7月3日，《自然》杂志在线发表了这项成果。

研究人员通过体内和体外动物模型实验表明，依赖于神经元活动的星形胶质细胞代谢激活由神经调节剂腺苷通过星形胶质细胞A2B受体介导。A2B受体的刺激招募了经典的环腺苷酸3′,5′-单磷酸–蛋白激酶A信号通路，导致星形胶质细胞葡萄糖代谢的快速激活和乳酸的释放，并补充了细胞外现成的能量底物池。在条件性删除星形胶质细胞中编码A2B受体基因的小鼠模型中，研究人员发现腺苷介导的代谢信号对于维持突触功能至关重要，特别是在高能量需求或能量供应减少的情况下。

敲低星形胶质细胞中A2B受体的表达导致大脑能量代谢的重大重编程，阻止海马体突触可塑性，严重损害识别记忆并扰乱睡眠。这些数据表明腺苷A2B受体作为星形胶质细胞的神经活动传感器，并显示cAMP信号在星形胶质细胞中调节大脑能量代谢以支持其基本功能，如睡眠和记忆。

据悉，大脑运算由数十亿神经细胞执行，依赖充足且不间断的营养和氧气供应。星形胶质细胞是神经元的广泛胶质邻居，负责大脑葡萄糖的摄取和代谢，但神经元与星形胶质细胞之间的代谢耦合机制尚未完全理解。

附：英文原文

Title: Adenosine signalling to astrocytes coordinates brain metabolism and function

Author: Theparambil, Shefeeq M., Kopach, Olga, Braga, Alice, Nizari, Shereen, Hosford, Patrick S., Sagi-Kiss, Virag, Hadjihambi, Anna, Konstantinou, Christos, Esteras, Noemi, Gutierrez Del Arroyo, Ana, Ackland, Gareth L., Teschemacher, Anja G., Dale, Nicholas, Eckle, Tobias, Andrikopoulos, Petros, Rusakov, Dmitri A., Kasparov, Sergey, Gourine, Alexander V.

Issue&Volume: 2024-07-03

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.

DOI: 10.1038/s41586-024-07611-w

Source: https://www.nature.com/articles/s41586-024-07611-w