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

Hailong Song, Przemyslaw McEwan, Kamar Ameen-Ali, Alexandra Tomasevich, Claire Kennedy-Dietrich, Alexander Palma, Edgardo Arroyo, Jean-Pierre Dolle, Victoria Johnson, William Stewart, Douglas Smith

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalActa Neuropathologica
DOIs
Publication statusPublished - 15 Sep 2022

Fingerprint

Dive into the research topics of 'Concussion leads to widespread axonal sodium channel loss and disruption of the node of Ranvier'. Together they form a unique fingerprint.

Cite this