Astrocyte calcium signaling: from observations to functions and the challenges therein

We provide an overview of recent progress on the study of astrocyte intracellular Ca(2+) signaling. We consider the methods that have been used to monitor astrocyte Ca(2+) signals, the various types of Ca(2+) signals that have been discovered (waves, microdomains, and intrinsic fluctuations), the approaches used to broadly trigger and block Ca(2+) signals, and, where possible, the proposed and demonstrated physiological roles for astrocyte Ca(2+) signals within neuronal microcircuits. Although important progress has been made, we suggest that further detailed work is needed to explore the biophysics and molecular mechanisms of Ca(2+) signaling within entire astrocytes, including their fine distal extensions, such as processes that interact spatially with neurons and blood vessels. Improved methods are also needed to mimic and block molecularly defined types of Ca(2+) signals within genetically specified populations of astrocytes. Moreover, it will be essential to study astrocyte Ca(2+) activity in vivo to distinguish between pharmacological and physiological activity, and to study Ca(2+) activity in situ to rigorously explore mechanisms. Once methods to reliably measure, mimic, and block specific astrocyte Ca(2+) signals with high temporal and spatial precision are available, researchers will be able to carefully explore the correlative and causative roles that Ca(2+) signals may play in the functions of astrocytes, blood vessels, neurons, and microcircuits in the healthy and diseased brain.