Abstract
Myelination within the central nervous system (CNS) is crucial for the conduction of action potentials by neurons. Variation in compact myelin morphology and the structure of the paranode are hypothesised to have significant impact on the speed of action potentials. There are, however, limited experimental data investigating the impact of changes in myelin structure upon conductivity in the central nervous system. We have used a genetic model in which myelin thickness is reduced to investigate the effect of myelin alterations upon action potential velocity. A detailed examination of the myelin ultrastructure of mice in which the receptor tyrosine kinase Tyro3 has been deleted showed that, in addition to thinner myelin, these mice have significantly disrupted paranodes. Despite these alterations to myelin and paranodal structure, we did not identify a reduction in conductivity in either the corpus callosum or the optic nerve. Exploration of these results using a mathematical model of neuronal conductivity predicts that the absence of Tyro3 would lead to reduced conductivity in single fibres, but would not affect the compound action potential of multiple myelinated neurons as seen in neuronal tracts. Our data highlight the importance of experimental assessment of conductivity and suggests that simple assessment of structural changes to myelin is a poor predictor of neural functional outcomes.
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Data availability
The code/software described in the paper will be freely available online at https://github.com/JordanChambers/compound-action-potential upon publication of this manuscript.
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Acknowledgements
Funding for this project was provided by The Trish Multiple Sclerosis Research Foundation to TJK and MB (17–0216), as well as an Australian Research Council Linkage Grant to CTON and BB (LP160100126). FB was supported by the Australian Government Research Training Program Scholarship. JDC was supported by the Australian Research Council Industrial Transformation Training Centre in Cognitive Computing for Medical Technologies (project number ICI70200030). CTON was supported by a Melbourne Research Fellowship. TJK was supported by an Investigator grant from the NH&MRC (#APP1175775). The Florey Institute of Neuroscience and Mental Health acknowledges the support received from the Victorian Government, in particular, the funding from the Operational Infrastructure Support Grant. We thank the Florey Neuroscience Microscopy Facility and the Centre for Advanced Histology & Microscopy (CAHM) at the Peter MacCallum Cancer Centre (Parkville, VIC, AU) for technical assistance.
Funding
Funding for this project was provided by The Trish Multiple Sclerosis Research Foundation to TJK and MB (17-0216), as well as an Australian Research Council Linkage Grant to CTON and BB (LP160100126). FB was supported by the Australian Government Research Training Program Scholarship. JDC was supported by the Australian Research Council Industrial Transformation Training Centre in Cognitive Computing for Medical Technologies (project number ICI70200030). CTON was supported by a Melbourne Research Fellowship. TJK was supported by an Investigator grant from the NH&MRC (#APP1175775). The Florey Institute of Neuroscience and Mental Health acknowledges the support received from the Victorian Government, in particular, the funding from the Operational Infrastructure Support Grant.
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Trevor J. Kilpatrick and Michele D. Binder designed research. Farrah Blades., Jordan D. Chambers, Timothy D. Aumann, Christine T.O. Nguyen, Vickie H.Y. Wong performed research. Farrah Blades., Jordan D. Chambers, Timothy D. Aumann, Christine T.O. Nguyen, Vickie H.Y. Wong, Andrea Aprico, Eze C. Nguyen, Bang V. Bui, David B. Grayden, Michele D. Binder analysed data. Farrah Blades., Jordan D. Chambers and Michele D. Binder wrote the paper.
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All animal procedures were performed in accordance with the approval of the Florey Institute of Neuroscience animal ethics committee and in accordance with the National Health and Medical Research Council (Australia) guidelines.
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429_2022_2489_MOESM1_ESM.docx
Online resource 1: Conduction velocities and geometric values for the single axon models from optic nerve and corpus callosum
429_2022_2489_MOESM2_ESM.pdf
Online resource 2: Repeated simulations of the compound action model produce minimal variability (a) The simulations for model WT and model Tyro3 KO were repeated 5 times without seeding the random generator. (b) The simulations of the effect of reducing the number of myelin lamellae by 3 were repeated 5 times without seeding the random number generator
429_2022_2489_MOESM3_ESM.zip
Online resource 3: This is the code used to simulate a single axon model and a compound action potential. The original single axon model was downloaded from https://github.com/AttwellLab/MyelinatedAxonModel. That model was based on previously published models (Arancibia-Cárcamo et al., 2017; Bakiri et al., 2011; Richardson et al., 2000). To run the model in MATLAB, following the instructions in the README.txt file. Example scripts are provided to reproduce results in Figure 5C and Figure 6A. These examples can easily be altered (see comments in the script files) to reproduce all results
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Blades, F., Chambers, J.D., Aumann, T.D. et al. White matter tract conductivity is resistant to wide variations in paranodal structure and myelin thickness accompanying the loss of Tyro3: an experimental and simulated analysis. Brain Struct Funct 227, 2035–2048 (2022). https://doi.org/10.1007/s00429-022-02489-8
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DOI: https://doi.org/10.1007/s00429-022-02489-8