The Active Astrocyte: Calcium Dynamics, Circuit Modulation, and Targets for Intervention.

Astrocytes, once considered passive support cells, have emerged as active participants in synaptic communication through Ca-dependent molecular signalling often referred to as gliotransmission. This review highlights the pioneering contributions of Giorgio Carmignoto, whose work has helped to redefine astrocytes as integral components of the tripartite synapse. Central to this paradigm shift is the role of astrocytic Ca²⁺ signalling in modulating synaptic activity, plasticity, and network behaviour. Carmignoto's research demonstrated that intracellular Ca fluctuations in astrocytes trigger the release of signalling molecules, influencing both excitatory and inhibitory neuronal circuits. These discoveries extended to network-level phenomena, implicating astrocytic Ca waves in pathological states like epilepsy. Technologically, Carmignoto advanced astroglial research by employing genetically encoded calcium indicators, optogenetic tools, and cutting-edge imaging methods, including multi-photon microscopy, to observe astrocyte activity in vivo. His work also contributed to automated data analysis pipelines that uncover fine-scale astrocytic microdomain dynamics. In the context of pathology, Carmignoto's studies related astrocytic dysfunction to epilepsy and dopaminergic dysregulation, suggesting new therapeutic avenues through astrocyte-specific interventions. Despite these advances, challenges remain in defining gliotransmitter mechanisms, understanding astrocyte heterogeneity, and developing tools for precise functional manipulation.