Potential and Realized Impact of Astroglia Ca^{2 +} Dynamics on Circuit Function and Behavior

Astroglia display a wide range of spontaneous and behavioral state-dependent Ca²⁺ dynamics. During heightened vigilance, noradrenergic signaling leads to quasi-synchronous Ca²⁺ elevations encompassing soma and processes across the brain-wide astroglia network. Distinct from this vigilance-associated global Ca²⁺ rise are apparently spontaneous fluctuations within spatially restricted microdomains. Over the years, several strategies have been pursued to shed light on the physiological impact of these signals including deletion of endogenous ion channels or receptors and reduction of intracellular Ca²⁺ through buffering, extrusion or inhibition of release. Some experiments that revealed the most compelling behavioral alterations employed chemogenetic and optogenetic manipulations to modify astroglia Ca²⁺ signaling. However, there is considerable contrast between these findings and the comparatively modest effects of inhibiting endogenous sources of Ca²⁺. In this review, we describe the underlying mechanisms of various forms of astroglia Ca²⁺ signaling as well as the functional consequences of their inhibition. We then discuss how the effects of exogenous astroglia Ca²⁺ modification combined with our knowledge of physiological mechanisms of astroglia Ca²⁺ activation could guide further refinement of behavioral paradigms that will help elucidate the natural Ca²⁺-dependent function of astroglia.