Stochastic Spatially-Extended Simulations Predict the Effect of ER Distribution on Astrocytic Microdomain Ca2+ Activity

Astrocytes are cells of the central nervous system that can regulate neuronal activity. Most astrocyte-neuron communication occurs at so-called tripartite synapses, where calcium signals are triggered in astrocytes by neuronal activity, resulting in the release of neuroactive molecules by the astrocyte. Most astrocytic Ca2+ signals occur in very thin astrocytic branchlets, containing low copy number of molecules, so that reactions are highly stochastic. As those sub-cellular compartments cannot be resolved by diffraction-limited microscopy techniques, stochastic reaction-diffusion computational approaches can give crucial insights on astrocyte activity. Here, we use our stochastic voxel-based model of IP3R-mediated Ca2+ signals to investigate the effect of the distance between the synapse and the closest astrocytic endoplasmic reticulum (ER) on neuronal activity-induced Ca2+ signals. Simulations are performed in three dimensional meshes characterized by various ER-synapse distances. Our results suggest that Ca2+ peak amplitude, duration and frequency decrease rapidly as ER-synapse distance increases. We propose that this effect mostly results from the increased cytosolic volume of branchlets that are characterized by larger ER-synapse distances. In particular, varying ER-synapse distance with constant cytosolic volume does not affect local Ca2+ activity. This study illustrates the insights that can be provided by three-dimensional stochastic reaction-diffusion simulations on the biophysical constraints that shape the spatio-temporal characteristics of astrocyte activity at the nanoscale.