Calcium Signaling in Oligodendrocyte Precursor Cells Mediated by Spontaneous and Evoked Responses: A Modeling Investigation

Abstract

Calcium (Ca2+) signaling has emerged as a central regulator of activity-dependent myelination in oligodendrocytes. These Ca2+ signals encompass both the stimulus-independent spontaneous Ca2+ local transients (SCaLTs) generated intrinsically in a voltage-independent manner or facilitated by the membrane voltage, as well as evoked responses triggered by ATP and glutamate release. To investigate the regulatory mechanisms underlying this combined spiking activity, we developed a stochastic spatiotemporal flux-balance model of Ca2+ transients in oligodendrocyte precursor cells (OPCs). The model incorporates all the relevant fluxes in these cells and integrates membrane voltage dynamics with a Ca2+-induced Ca2+-release (CICR) mechanism using parameters fitted to Ca2+ fluorescence recordings. The model reproduced the intrinsic and voltage-facilitated SCaLTs in OPCs in the absence of purinergic and glutamatergic receptors, and captured the three distinct patterns of evoked Ca2+ responses induced by ATP and glutamate identified using machine classifier. The model highlighted the role of ATP and glutamate concentrations in generating these clusters, and showed that the fast dynamics of CICR is key to producing these evoked responses. Further analysis of the model also revealed that voltage-gated L- and T-type Ca2+ channels slightly increase the frequency of SCaLTs, while stimulation with ATP and glutamate, using randomly distributed pulses mimicking in vivo conditions, leads to an increase in both the amplitudes of Ca2+ spikes (i.e., the combination of SCaLTs and evoked responses) and the prevalence of wide spikes, especially upon glutamate stimulation. Bifurcation analysis of the deterministic version of the model, in the absence of diffusion, demonstrated that ATP and glutamate stimulation can shift the system into an oscillatory regime, thereby increasing the deterministic component of SCaLT dynamics. This study thus offers a comprehensive representation of OPC Ca2+ transients linking recorded in vitro behaviors to in vivo dynamics. Author summaryOligodendrocytes are glial cells in the central nervous system that form myelin, the insulating sheath enabling rapid nerve signal transmission. Myelination is a dynamic process influenced by neuronal activity, with calcium (Ca2+) signaling emerging as a key regulator. These signals include spontaneous local Ca2+ transients (SCaLTs), generated intrinsically or facilitated by membrane voltage, as well as evoked responses triggered by neurotransmitters like ATP and glutamate. To understand how these signals arise and interact, we combined experimental recordings of Ca2+ activity in oligodendrocyte precursor cells (OPCs) with a data-driven biophysical model. The model incorporates stochastic Ca2+ fluxes, membrane voltage dynamics, and ca-induced Ca2+-release (CICR), allowing us to simulate diverse patterns of Ca2+ transients. Our simulations reproduced both intrinsic and voltage-facilitated SCaLTs and captured three distinct evoked response types induced by ATP and glutamate. We found that voltage-gated Ca2+ channels slightly enhance SCaLT frequency, while rapid CICR dynamics are critical for shaping the amplitude and timing of evoked signals. Furthermore, neurotransmitter stimulation can drive the system into an oscillatory regime, increasing the deterministic structure of Ca2+ transients. This work offers a mechanistic framework linking intracellular Ca2+ dynamics to the regulation of activity-dependent myelination in OPCs.