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Concussion leads to widespread axonal sodium channel loss and disruption of the node of Ranvier

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Abstract

Despite being a major health concern, little is known about the pathophysiological changes that underly concussion. Nonetheless, emerging evidence suggests that selective damage to white matter axons, or diffuse axonal injury (DAI), disrupts brain network connectivity and function. While voltage-gated sodium channels (NaChs) and their anchoring proteins at the nodes of Ranvier (NOR) on axons are key elements of the brain’s network signaling machinery, changes in their integrity have not been studied in context with DAI. Here, we utilized a clinically relevant swine model of concussion that induces evolving axonal pathology, demonstrated by accumulation of amyloid precursor protein (APP) across the white matter. Over a two-week follow-up post-concussion with this model, we found widespread loss of NaCh isoform 1.6 (Nav1.6), progressive increases in NOR length, the appearance of void and heminodes and loss of βIV-spectrin, ankyrin G, and neurofascin 186 or their collective diffusion into the paranode. Notably, these changes were in close proximity, yet distinct from APP-immunoreactive swollen axonal profiles, potentially representing a unique, newfound phenotype of axonal pathology in DAI. Since concussion in humans is non-fatal, the clinical relevance of these findings was determined through examination of post-mortem brain tissue from humans with higher levels of acute traumatic brain injury. Here, a similar loss of Nav1.6 and changes in NOR structures in brain white matter were observed as found in the swine model of concussion. Collectively, this widespread and progressive disruption of NaChs and NOR appears to be a form of sodium channelopathy, which may represent an important substrate underlying brain network dysfunction after concussion.

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Acknowledgements

Here, we thank Drs. Stephen Waxman, Sulayman Dib-Hajj, and Shujun Liu from Yale University, Dr. Matthew Rasband from Baylor College of Medicine, and Dr. Peter Brophy from The University of Edinburgh for providing primary antibodies used in this study. We also thank Dr. David F. Meaney for using the Leica SP5 confocal microscope, and Cell & Developmental Biology (CDB) microscopy core at University of Pennsylvania for using the Zeiss LSM 880 with Airyscan confocal microscope and Imaris software (GraphPad, Bitplane, v.9.7) with the help from Drs. Andrea Stout, Xinyu Zhao, and Matthew J. Gastinger for the initial setup. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding

This research was made available with the following support from National Institutes of Health grants R01NS092398 (DHS), R01NS038104 (DHS), R01NS094003 (DHS), R01EB021293 (DHS), U54NS115322 (WS and DHS), as well as support from Paul G. Allen Family Foundation (DHS) and the Pennsylvania Department of Health Consortium on Traumatic Brain Injury 4100077083 (DHS).

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Authors and Affiliations

  1. Department of Neurosurgery, Center for Brain Injury and Repair, University of Pennsylvania, 3320 Smith Walk, 105 Hayden Hall, Philadelphia, PA, 19104, USA

    Hailong Song, Przemyslaw P. McEwan, Alexandra Tomasevich, Alexander Palma, Edgardo J. Arroyo, Jean-Pierre Dolle, Victoria E. Johnson & Douglas H. Smith

  2. School of Neuroscience and Psychology, University of Glasgow, Glasgow, G12 8QQ, UK

    Kamar E. Ameen-Ali, Claire Kennedy-Dietrich & William Stewart

  3. Department of Neuropathology, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK

    William Stewart

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Contributions

Each author’s contributions to the paper are listed. Conceptualization: HS, PPM, DHS; Methodology: HS, PPM, KEAA, AT, CKD, AP, EJA, VEJ, WS, DHS; Investigation: HS, PPM, KEAA, WS, DHS; Visualization: HS; Funding acquisition: WS, DHS; Supervision: HS, VEJ, JPD, WS, DHS; Writing—original draft: HS, DHS; Writing—review & editing: HS, JPD, WS, DHS.

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Correspondence to Douglas H. Smith.

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Song, H., McEwan, P.P., Ameen-Ali, K.E. et al. Concussion leads to widespread axonal sodium channel loss and disruption of the node of Ranvier. Acta Neuropathol 144, 967–985 (2022). https://doi.org/10.1007/s00401-022-02498-1

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