Wannan Tang

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.

Brain edema is a feared complication to disorders and insults affecting the brain. It can be fatal if the increase in intracranial pressure is sufficiently large to cause brain herniation. Moreover, accruing evidence suggests that even slight elevations of intracranial pressure have adverse effects, for instance on brain perfusion. The water channel aquaporin‐4 (AQP4), densely expressed in perivascular astrocytic endfeet, plays a key role in brain edema formation. Using two‐photon microscopy, we have studied AQP4‐mediated swelling of astrocytes affects capillary blood flow and intracranial pressure (ICP) in unanesthetized mice using a mild brain edema model. We found improved regulation of capillary blood flow in mice devoid of AQP4, independently of the severity of ICP increase. Furthermore, we found brisk AQP4‐dependent astrocytic Ca 2+ signals in perivascular endfeet during edema that may play a role in the perturbed capillary blood flow dynamics. The study suggests that astrocytic endfoot swelling and pathological signaling disrupts microvascular flow regulation during brain edema formation.