Increased membrane Ca²⁺ permeability drives astrocytic Ca²⁺ dynamics during neuronal stimulation at excitatory...

Astrocytes are intricately involved in the activity of neural circuits; however, their basic physiology of interacting with nearby neurons is not well established. Using two-photon imaging of neurons and astrocytes during higher frequency stimulation of hippocampal CA3-CA1 Schaffer collateral (Scc) excitatory synapses, we could show that increasing levels of released glutamate accelerated local astrocytic Ca²⁺ elevation. However, blockage of glutamate transporters did not abolish this astrocytic Ca²⁺ response, suggesting that astrocytic Ca²⁺ elevation is indirectly associated with an uptake of extracellular glutamate. However, during the astrocytic glutamate uptake, the Na⁺ /Ca²⁺ exchanger (NCX) reverse mode was activated, and mediated extracellular Ca²⁺ entry, thereby triggering the internal release of Ca²⁺ . In addition, extracellular Ca²⁺ entry via membrane P2X receptors further facilitated astrocytic Ca²⁺ elevation via ATP binding. These findings suggest a novel mechanism of activity induced Ca²⁺ permeability increases of astrocytic membranes, which drives astrocytic responses during neuronal stimulation of CA3-CA1 Scc excitatory synapses.