Increased membrane Ca 2+ permeability drives astrocytic Ca 2+ dynamics during neuronal stimulation at excitatory synapses.

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 Ca 2+ elevation. However, blockage of glutamate transporters did not abolish this astrocytic Ca 2+ response, suggesting that astrocytic Ca 2+ elevation is indirectly associated with an uptake of extracellular glutamate. However, during the astrocytic glutamate uptake, the Na + /Ca 2+ exchanger (NCX) reverse mode was activated, and mediated extracellular Ca 2+ entry, thereby triggering the internal release of Ca 2+ . In addition, extracellular Ca 2+ entry via membrane P2X receptors further facilitated astrocytic Ca 2+ elevation via ATP binding. These findings suggest a novel mechanism of activity induced Ca 2+ permeability increases of astrocytic membranes, which drives astrocytic responses during neuronal stimulation of CA3-CA1 Scc excitatory synapses.