Calcium Signals in Astrocyte Microdomains, a Decade of Great Advances

The glial cells astrocytes have long been recognized as important neuron-supporting elements in brain development, homeostasis, and metabolism. After the discovery that the reciprocal communication between astrocytes and neurons is a fundamental mechanism in the modulation of neuronal synaptic communication, over the last two decades astrocytes became a hot topic in neuroscience research. Crucial to their functional interactions with neurons are the cytosolic Ca²⁺ elevations that mediate gliotransmission. Large attention has been posed to the so-called Ca²⁺microdomains, dynamic Ca²⁺ changes spatially restricted to fine astrocytic processes including perisynaptic astrocytic processes (PAPs). With presynaptic terminals and postsynaptic neuronal membranes, PAPs compose the tripartite synapse. The distinct spatial-temporal features and functional roles of astrocyte microdomain Ca²⁺ activity remain poorly defined. However, thanks to the development of genetically encoded Ca²⁺ indicators (GECIs), advanced microscopy techniques, and innovative analytical approaches, Ca²⁺ transients in astrocyte microdomains were recently studied in unprecedented detail. These events have been observed to occur much more frequently (∼50-100-fold) and dynamically than somatic Ca²⁺ elevations with mechanisms that likely involve both IP₃-dependent and -independent pathways. Further progress aimed to clarify the complex, dynamic machinery responsible for astrocytic Ca²⁺ activity at microdomains is a crucial step in our understanding of the astrocyte role in brain function and may also reveal astrocytes as novel therapeutic targets for different brain diseases. Here, we review the most recent studies that improve our mechanistic understanding of the essential features of astrocyte Ca²⁺ microdomains.