Characterizing spontaneous Ca2+ local transients in OPCs using computational modeling

Abstract

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 contributions 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 information in their frequency, and (4) their slow baseline oscillations could be due to the stochastic slow clustering of inositol-trisphosphate 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 excitability, 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⁺ exchange decreases (increases) SCaLTs. Taken together, these results provide a quantitative framework for SCaLT formation in oligodendrocyte precursor cells.