Characterizing the role of Ca2+ fluxes in defining fast and slow components of spontaneous Ca2+ local transients in OPCs using computational modeling

Abstract

1Spontaneous Ca2+ local transients (SCaLTs) in isolated oligodendrocyte precursor cells (OPCs) are largely regulated by the following fluxes: store-operated Ca2+ entry (SOCE), Na+/Ca2+ exchange (NCX), Ca2+ pumping through Ca2+-ATPases, and Ca2+-induced Ca2+-release through Ryanodine receptors (RyR) and inositoltriphosphate receptors (IP3R). However, the relative contributions of these fluxes in mediating fast spiking and 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 ion 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 interspike intervals (ISI) against ISI averages of multiple model and experimental realizations we revealed that: SCaLTs exhibit very similar characteristics between the two datasets, they are mostly random, they encode information in their frequency, and the slow baseline oscillations could be due to the stochastic slow clustering of IP3R (modeled as an Ornstein-Uhlenbeck noise process). Bifurcation analysis of a deterministic temporal version of the model shows 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 demonstrate that blocking each flux reduces SCaLTs frequency and that the reverse (forward) mode of NCX decreases (increases) SCaLTs. Taken together, these results provide a quantitative framework for SCaLT formation in OPCs.