Control of Ca2+ signals by astrocyte nanoscale morphology at tripartite synapses

• Published in: Glia 2022-12, Vol.70 (12), p.2378-2391
• Main Authors: Denizot, Audrey, Arizono, Misa, Nägerl, U. Valentin, Berry, Hugues, De Schutter, Erik
• Format: Article
• Language: English
• Subjects: Astrocytes; Calcium ions; calcium microdomains; Calcium signalling; Computational neuroscience; Information flow; intracellular signaling; Life Sciences; Morphology; nano‐morphology; Neurobiology; Neurons and Cognition; Neurotransmitter release; Neurotransmitters; reaction–diffusion simulations; Signal processing; Software; Swelling; Synapses
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.24258

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 idealized 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. Main Points Astrocyte nano‐morphology favors the compartmentalization of biochemical signals. This compartmentalization promotes local Ca2+ activity and signal propagation robustness. In contrast, its pathological remodeling upon swelling attenuates Ca2+ activity.