The brain, a complex and sophisticated organ, relies on the interaction of billions of neurons, and its computing power relies on an adequate and uninterrupted supply of nutrients and oxygen. As neighbors of neurons, astrocytes dominate the brain's glucose uptake and metabolism. However, the metabolic coupling mechanism between neurons and astrocytes, that is, how to quickly provide energy support when the energy demand of neurons surges, is not yet fully understood.
Recently, scientists from University College London published a research paper titled "Adenosine signalling to astrocytes coordinates brain metabolism and function" in Nature. This article reveals an important metabolic pathway: the metabolic activation of astrocytes dependent on neuronal activity is mediated by adenosine acting on the A2B receptor of astrocytes. The research team confirmed through in vitro and in vivo animal model experiments that the stimulation of A2B receptors triggered the classic cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway, which rapidly activated the glucose Metabolism of astrocytes and released lactate. These lactates replenish the extracellular pool of readily available energy substrates, providing neurons with much-needed energy.
Using a conditional knockout mouse model in which the A2B receptor gene was deleted in astrocytes, the researchers found that adenosine-mediated metabolic signaling is critical for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Loss of A2B receptors leads to significant reprogramming of brain energy metabolism, impedes synaptic plasticity in the hippocampus, severely impairs recognition memory, and disrupts sleep.
Fig.1 Neuronal activity-dependent recruitment of cAMP–PKA signalling in astrocytes is mediated by adenosine A2B receptors. (Theparambil, et al., 2024)
Neurons in the brain lack significant metabolic reserves and require a constant supply of energy. Astrocytes rapidly activate Glucose metabolism by storing chemical energy (such as glycogen) and responding to increased neuronal activity. This metabolic coupling is essential for supporting the function of neural circuits that control core behaviors. Studies have shown that metabolic activation of astrocytes leads to the production and release of lactate, which rapidly increases lactate concentrations and supplements the extracellular pool of readily available energy substrates. A large amount of experimental evidence supports that the transfer of lactate from astrocytes to neurons is important for metabolic support of neuronal function.
In peripheral tissues such as the liver and muscles, increased energy expenditure rapidly recruits intracellular glucose reserves through the action of hormones such as Glucagon and catecholamines and activates the classic cAMP-PKA signaling pathway. In the brain, the cAMP-PKA signaling pathway in astrocytes is regulated by adenosine and coordinates brain energy metabolism and function. Adenosine, as a neuromodulator, triggers a series of signaling events through the A2B receptor, enabling astrocytes to rapidly respond to the energy needs of neurons, release lactate, maintain synaptic function, and support basic brain functions such as memory and sleep.
This study revealed that Adenosine A2B receptor act as an astrocytic sensor of neural activity, regulating brain energy metabolism through the cAMP signaling pathway to support its basic functions such as sleep and memory. The key role of astrocytes in brain energy metabolism is highlighted, further revealing the complex and subtle metabolic coupling mechanism between neurons and astrocytes. This discovery points the way for future research, and scientists will continue to explore the specific mechanisms of this signaling pathway and reveal more about the importance of astrocytes in brain function. This will help us better understand the relationship between brain energy metabolism and neural activity, thereby promoting the development of neuroscience.
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