Song, H. et al. (2022) Concussion leads to widespread axonal sodium channel loss and disruption of the node of Ranvier. Acta Neuropathologica, 144(5), pp. 967-985. (doi: 10.1007/s00401-022-02498-1) (PMID:36107227)
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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.
Item Type: | Articles |
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Additional Information: | 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). |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Stewart, Dr William and Ameen-Ali, Dr Kamar |
Authors: | Song, H., McEwan, P. P., Ameen-Ali, K. E., Tomasevich, A., Kennedy-Dietrich, C., Palma, A., Arroyo, E. J., Dolle, J.-P., Johnson, V. E., Stewart, W., and Smith, D. H. |
College/School: | College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
Journal Name: | Acta Neuropathologica |
Publisher: | Springer |
ISSN: | 0001-6322 |
ISSN (Online): | 1432-0533 |
Published Online: | 15 September 2022 |
Copyright Holders: | Copyright © 2022 The Authors |
First Published: | First published in Acta Neuropathologica 144(5): 967-985 |
Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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