Depletion of extracellular Ca²⁺ prompts astroglia to moderate synaptic network activity

Over the past decade, rapid signal exchange between astroglia and neurons across the interstitial space emerged as an essential element of synaptic circuit functioning in the brain. How and where exactly this exchange occurs in various physiological scenarios and the underlying cellular cascades remain a subject of intense study. The excitatory neurotransmitter glutamate and the inhibitory neurotransmitter γ-aminobutyric acid are thought to be the primary signal carriers that are regularly dispatched by active synapses to engage target receptors and transporters on the surface of astrocytes. New evidence identifies another ubiquitous messenger, extracellular calcium ions (Ca(2+)), which can report neural network activity to astroglia. Astrocytes in the hippocampus can respond to activity-induced partial Ca(2+) depletion in the extracellular space by generating prominent intracellular Ca(2+) waves. The underlying Ca(2+) sensing mechanism is proposed to involve the opening of the hemichannel connexin 43 in astrocytes, which in turn triggers the release of adenosine triphosphate to boost the activity of inhibitory interneurons, thus potentially providing negative feedback to tame excessive excitatory activity of neural circuits.