LAUSR

Much of the Ca2+ activity in astrocytes is spatially restricted to microdomains and occurs in fine processes that form a complex anatomical meshwork, the so-called spongiform domain. A growing body of literature indicates that those astrocytic Ca2+ signals can influence the activity of neuronal synapses and thus tune the flow of information through neuronal circuits. Because of technical difficulties in accessing the small spatial scale involved, the role of astrocyte morphology on Ca2+ microdomain activity remains poorly understood. Here, we use computational tools and realistic 3D geometries of fine processes based on recent super-resolution microscopy data to investigate the mechanistic link between astrocytic nanoscale morphology and local Ca2+ activity. Simulations demonstrate that the nano-morphology of astrocytic processes powerfully shapes the spatio-temporal properties of Ca2+ signals and promotes local Ca2+ activity. The model predicts that this effect is attenuated upon astrocytic swelling, hallmark of brain diseases, which we confirm experimentally in hypo-osmotic conditions. Upon repeated neurotransmitter release events, the model predicts that swelling hinders astrocytic signal propagation. Overall, this study highlights the influence of the complex morphology of astrocytes at the nanoscale and its remodeling in pathological conditions on neuron-astrocyte communication at so-called tripartite synapses, where astrocytic processes come into close contact with pre- and postsynaptic structures. Significance statement Astrocytes finely regulate the information flow at synapses via spatially-restricted Ca2+ signals in perisy-naptic astrocytic processes (PAPs). Most PAPs form a complex anatomical meshwork that likely influences local Ca2+ activity, yet cannot be resolved by diffraction-limited light microscopy. Because of the spatial scale involved, the mechanistic link between PAP nano-morphology and Ca2+ activity remains unclear. Here, we perform computational simulations in 3D PAP meshes derived from recent super-resolution microscopy data. Our model predicts that the nano-architecture of processes effectively increases local Ca2+ activity, while its pathological remodelling under hypo-osmotic conditions decreases local activity, which we confirm experimentally. This study sheds new light on the role of the nano-anatomy of astrocytic processes in shaping local Ca2+ activity in health and disease.