Calcium Signaling in Oligodendrocyte Precursor Cells Mediated by Spontaneous and Evoked Responses: A Modeling Investigation
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Calcium (Ca 2+ ) signaling has emerged as a central regulator of activity-dependent myelination in oligodendrocytes. These Ca 2+ signals encompass both the stimulus-independent spontaneous Ca 2+ 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 Ca 2+ transients in oligodendrocyte precursor cells (OPCs). The model incorporates all the relevant fluxes in these cells and integrates membrane voltage dynamics with a Ca 2+ -induced Ca 2+ -release (CICR) mechanism using parameters fitted to Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ transients linking recorded in vitro behaviors to in vivo dynamics.
Author summary
Oligodendrocytes 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 (Ca 2+ ) signaling emerging as a key regulator. These signals include spontaneous local Ca 2+ 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 Ca 2+ activity in oligodendrocyte precursor cells (OPCs) with a data-driven biophysical model. The model incorporates stochastic Ca 2+ fluxes, membrane voltage dynamics, and ca-induced Ca 2+ -release (CICR), allowing us to simulate diverse patterns of Ca 2+ 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 Ca 2+ 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 Ca 2+ transients. This work offers a mechanistic framework linking intracellular Ca 2+ dynamics to the regulation of activity-dependent myelination in OPCs.
