Astrocytic Glucose Sensing Drives Synaptic Depression under Metabolic Stress

Glucose is the primary energy source for the brain, and its continuous supply is essential for neuronal function. Astrocytes play a pivotal role in brain energy metabolism by mediating glucose uptake, sensing metabolic fluctuations, and modulating synaptic activity. However, astrocyte responses to transient glucose deprivation remain incompletely understood. Here, we demonstrate that astrocytic glucose uptake is crucial for network adaptation to metabolic stress. Using electrophysiology and calcium imaging approaches, we show that glucose deprivation depresses hippocampal synaptic transmission through an astrocyte-dependent mechanism that involves decreased glucose transporter 1 (GLUT1)-facilitated extracellular glucose uptake, intracellular calcium elevations, and ATP/adenosine-mediated signaling, which leads to excitatory neurotransmission depression via A1 receptors. Moreover, astrocyte-specific GLUT1 depletion prevents astrocytic responses to glucose deprivation and precludes the effects of glucose deprivation on synaptic transmission, thereby indicating that GLUT1-dependent glucose uptake is involved in astrocyte-mediated modulation of synaptic function. These findings extend the concept of astrocytic metabolic regulation beyond regions canonically classified as glucose-sensing and establish astrocytes as key integrators of energy availability and synaptic function. Our study provides new insights into the role of astrocytes in brain energy homeostasis and identifies potential therapeutic targets for metabolic disorders affecting the nervous system.