P128 Electrodiffusion and voltage dynamics in the periaxonal space with spatially detailed finite-element simulations
Tim M. Kamsma*1,2, R. van Roij1, Maarten H.P. Kole3,4
1Institute for Theoretical Physics, Utrecht University, Utrecht, The Netherlands
2Mathematical Institute, Utrecht University, Utrecht, The Netherlands
3Department of Axonal Signalling, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands
4Cell biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
*Email: t.m.kamsma@uu.nl
Introduction
The submyelin, or periaxonal, space was long considered to be an inert region of the internode. This view has been revised over recent years, as evidence accumulated that the periaxonal region plays important roles in both the electrical saltatory conduction of the action potential [1] and in chemical axo-myelinic cell signalling [2]. The nanoscale dimensions of the periaxonal space makes experimental investigations into the electrochemical dynamics extremely challenging. Traditional cable theory models, though informative for electrical properties [1], do not provide the spatial resolution nor the appropriate ionic transport equations to resolve the complex electrodiffusion profiles inherent to such highly confined geometries.
Methods
To investigate the electrochemical dynamics of axon-myelin spaces, we developed a computational model that employs detailed finite-element simulations to numerically resolve first-principles ion transport equations within a biologically accurate geometry of a myelinated axon. Membrane currents were implemented through standard Hodgkin-Huxley-like voltage-dependent ion channel equations, while outside of the membrane all concentrations and voltages were fully governed by the Poisson-Nernst-Planck equations. These coupled physical equations were numerically solved with the software package COMSOL. The results were compared to traditional simulations using a double-cable model of the NEURON software package.
Results
Our computational model autonomously generated biophysically accurate action potentials and spatially resolved all ionic and voltage dynamics. Without clearance mechanisms, periaxonal potassium accumulation of up to ~10 mM was predicted for a single action potential. Consequently, we investigated and revealed possible potassium clearance pathways via the oligodendrocyte-myelin complex. More generally, as all physical quantities are fully resolved with high spatial resolution, this model can flexibly provide other desired insights within the entire modelled geometry. Furthermore, molecular transport, chemical reactions, and fluid flow can be coupled to the same model, which therefore can serve as a versatile platform for future expansions.
Discussion
Although our simulations can probe regions that are experimentally difficult to access, the model still required parameter inputs and is therefore also constrained by the limited experimental data. Future simulations and biological 3D EM data will need to advance in tandem to fully investigate the dynamics in this region. The geometry of the model assumed a rotational symmetry, which considerably simplified the model, but is not entirely biologically accurate. Lastly, we did not resolve the physics within membranes, as this requires molecular scale simulations. However, since phenomenological Hodgkin-Huxley-like membrane current equations are well-tested, we expect that the modelled ionic fluxes are quantitatively accurate.
Acknowledgements
This work was supported by the Science for Sustainability Graduate Programme of Utrecht University.
References
1.Cohen, C. C., Popovic, M. A., Klooster, J., Weil, M. T., Möbius, W., Nave, K. A., & Kole, M. H. (2020).Saltatory conduction along myelinated axons involves a periaxonal nanocircuit.Cell,180(2), 311-322.https://doi.org/10.1016/j.cell.2019.11.039
2.Micu, I., Plemel, J. R., Caprariello, A. V., Nave, K. A., & Stys, P. K. (2018).Axo-myelinic neurotransmission: a novel mode of cell signalling in the central nervous system.Nature Reviews Neuroscience,19(1), 49-58.https://doi.org/10.1038/nrn.2017.128
