Astrocytes, a glial cell type of the central nervous system, have emerged as detectors and regulators of neuronal information processing. Astrocyte excitability resides in transient variations of free cytosolic calcium concentration over a range of temporal and spatial scales, from sub-microdomains to waves propagating throughout the cell. Despite extensive experimental approaches, it is not clear how these signals are transmitted to and integrated within an astrocyte. The localization of the main molecular actors and the geometry of the system, including calcium channels IP3R spatial organization, are deemed essential. However, as most calcium signals occur in astrocytic ramifications that are too fine to be resolved by conventional light microscopy, most of those spatial data are unknown and computational modeling remains the only methodology to study this issue. Here, we propose an IP3R-mediated calcium signaling model for dynamics in such small sub-cellular volumes. To account for the expected stochasticity and low copy numbers, our model is both spatially explicit and particle-based. Extensive simulations show that spontaneous calcium signals arise in the model via the interplay between excitability and stochasticity. The model reproduces the main forms of calcium signals and indicates that their frequency crucially depends on the spatial organization of the IP3R channels. Importantly, we show that two processes expressing exactly the same calcium channels can display different types of calcium signals depending on channels spatial organization. Our model with realistic process volume and calcium concentrations successfully reproduces spontaneous calcium signals that we measured in calcium micro-domains with confocal microscopy. To our knowledge, this model is the first model suited to investigate calcium dynamics in fine astrocytic processes and to propose plausible mechanisms responsible for their variability. Introduction 1 Astrocytes were first characterized as non-excitable cells of the central nervous 2 system since, although they express voltage-gated channels [1], they do not exhibit 3 electrical excitability [2]. Astrocytes excitability instead results from variations of 4 cytosolic calcium concentration [3]. At the cellular level, those calcium signals emerge in 5 astrocytes in response to synaptic activity and may cause the release of molecules called 6 1 gliotransmitters such as glutamate, ATP, tumor necrosis factor-α, or D-serine, which 7can modulate synaptic transmission [4][5][6][7] and vasoconstriction/vasodilatation [8][9][10][11]. 8 This close association of astrocytes to pre-and post-synaptic elements, both 9 structurally and functionally, is referred to as tripartite synapse (see e.g. [12][13][14][15] for 10 reviews on tripartite synapses and the associated controversies). On a larger scale, 11 astrocytic calcium signals can modulate neuronal synchronization and firing 12 pattern [16][17][18] and have been observed in vivo in response to external stimuli [19,20]. 13 Altogether, those obse...