Characterizing spontaneous Ca2+ local transients in OPCs using computational modeling

Spontaneous Ca2+ local transients (SCaLTs) in isolated oligodendrocyte precursor cells are largely regulated by the following fluxes: store-operated Ca2+ entry (SOCE), Na+/Ca2+ exchange, Ca2+ pumping through Ca2+-ATPases, and Ca2+-induced Ca2+-release through ryanodine receptors and inositol-trisphosphate receptors. However, the relative contribu-tions of these fluxes in mediating fast spiking and the slow baseline oscillations seen in SCaLTs remain incompletely understood. Here, we developed a stochastic spatiotemporal computational model to simulate SCaLTs in a homogeneous medium with ionic flow between the extracellular, cytoplasmic, and endoplasmic-reticulum compartments. By simulating the model and plotting both the histograms of SCaLTs obtained experimentally and from the model as well as the standard deviation of inter-SCaLT intervals against inter-SCaLT interval averages of multiple model and experimental realizations, we revealed the following: (1) SCaLTs exhibit very similar characteristics between the two data sets, (2) they are mostly random, (3) they encode informa-tion in their frequency, and (4) their slow baseline oscillations could be due to the stochastic slow clustering of inositol-trisphos-phate receptors (modeled as an Ornstein-Uhlenbeck noise process). Bifurcation analysis of a deterministic temporal version of the model showed that the contribution of fluxes to SCaLTs depends on the parameter regime and that the combination of excit-ability, stochasticity, and mixed-mode oscillations are responsible for irregular spiking and doublets in SCaLTs. Additionally, our results demonstrated that blocking each flux reduces SCaLTs' frequency and that the reverse (forward) mode of Na+/Ca2+ ex-change decreases (increases) SCaLTs. Taken together, these results provide a quantitative framework for SCaLT formation in oligodendrocyte precursor cells.

Automated summary

This study developed a stochastic spatiotemporal computational model to simulate spontaneous Ca2+ local transients (SCaLTs) in isolated oligodendrocyte precursor cells. By comparing the model simulation with experimental data, the study found that SCaLTs exhibited similar characteristics between the two datasets, were mostly random, and encoded information in their frequency. The study also suggested that the slow baseline oscillations of SCaLTs could be attributed to the stochastic slow clustering of inositol-trisphosphate receptors.