A modelling study to dissect the potential role of voltage-gated ion channels in activity-dependent conduction velocity changes as identified in small fiber neuropathy patients.
Maxion, Anna; Kutafina, Ekaterina; Dohrn, Maike Fet al.
2023 • In Frontiers in Computational Neuroscience, 17, p. 1265958
C-fiber axon; in-silico model; microneurography; neuron; neuropathic pain; simulation; voltage-gated ion channels; Activity-dependent; Conduction velocity; In-silico models; Ion channel; Membrane potentials; Voltage gated ion channels; Neuroscience (miscellaneous); Cellular and Molecular Neuroscience
Abstract :
[en] [en] OBJECTIVE: Patients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechano-insensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect specific molecular mechanisms in humans. We used an in-silico model to elucidate molecular causes of CMi dysfunction as observed in single nerve fiber recordings (microneurography) of SFN patients.
APPROACH: We analyzed microneurography data from 97 CMi-fibers from healthy individuals and 34 of SFN patients to identify activity-dependent changes in conduction velocity. Using the NEURON environment, we adapted a biophysical realistic preexisting CMi-fiber model with ion channels described by Hodgkin-Huxley dynamics for identifying molecular mechanisms leading to those changes. Via a grid search optimization, we assessed the interplay between different ion channels, Na-K-pump, and resting membrane potential.
MAIN RESULTS: Changing a single ion channel conductance, Na-K-pump or membrane potential individually is not sufficient to reproduce in-silico CMi-fiber dysfunction of unchanged activity-dependent conduction velocity slowing and quicker normalization of conduction velocity after stimulation as observed in microneurography. We identified the best combination of mechanisms: increased conductance of potassium delayed-rectifier and decreased conductance of Na-K-pump and depolarized membrane potential. When the membrane potential is unchanged, opposite changes in Na-K-pump and ion channels generate the same effect.
SIGNIFICANCE: Our study suggests that not one single mechanism accounts for pain-relevant changes in CMi-fibers, but a combination of mechanisms. A depolarized membrane potential, as previously observed in patients with neuropathic pain, leads to changes in the contribution of ion channels and the Na-K-pump. Thus, when searching for targets for the treatment of neuropathic pain, combinations of several molecules in interplay with the membrane potential should be regarded.
Disciplines :
Physical, chemical, mathematical & earth Sciences: Multidisciplinary, general & others
Author, co-author :
Maxion, Anna; Research Group Neuroscience, Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University, Aachen, Germany
Kutafina, Ekaterina; Institute of Medical Informatics, Medical Faculty, RWTH Aachen University, Aachen, Germany
Dohrn, Maike F; Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany
Sacré, Pierre ; Université de Liège - ULiège > Département d'électricité, électronique et informatique (Institut Montefiore) > Robotique intelligente
Lampert, Angelika; Institute of Neurophysiology, Uniklinik RWTH Aachen University Aachen, Aachen, Germany
Tigerholm, Jenny; Joint Research Center for Computational Biomedicine, RWTH Aachen, Aachen, Germany
Namer, Barbara; Research Group Neuroscience, Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University, Aachen, Germany ; Institute of Neurophysiology, RWTH Aachen University, Aachen, Germany ; Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Erlangen, Germany
Language :
English
Title :
A modelling study to dissect the potential role of voltage-gated ion channels in activity-dependent conduction velocity changes as identified in small fiber neuropathy patients.
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. AM ans AL are funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 368482240/GRK2416. JT is supported by the Center for Neuroplasticity and Pain is supported by the Danish National Research Foundation (DNRF121). BN is supported by a grant from the Interdisciplinary Center for Clinical Research within the Faculty of Medicine at the RWTH Aachen University, DFG NA 9707/1. This work was funded by the Deutsche Forschungsgemeinschaft German Research Foundation LA 2740/3–1, 363055819/GRK2415 Mechanobiology of 3D epithelial tissues (ME3T). AL, BN and MD are supported by a grant from the Interdisciplinary Center for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF TN1-1/IA 532001, IZKF TN1-1IA 532002, IZKF TN1-6/IA 532006, and IZKF TN1-9/IA 532009).
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