Traumatic Brain Injury and Axonal Sodium Loading: Modeling the Impact of Left-Shifted Nav Channel Operation at Blebbed Nodes of Ranvier

Abstract

Traumatic brain injury like stretch immediately (<2 min) and irreversibly causes a TTX-sensitive axonal [Ca2+] increase that, in situ, underlies an untreatable pathology, diffuse axonal injury. Nav1.6-expressing mammalian cells, we showed, immediately (<2 min) exhibit TTX-sensitive Na+-leak following traumatic stretch (Wang et al 2009 Am J Physiol 297: in press). In situ, even mild axonal stretch injury can trigger adverse positive feedback so that leaks progress irreversibly to lethality. Though clinical trials are underway using Nav channel blockers that might reduce the severity of this outcome, molecular understanding of Nav channel damage has been lacking. Recently, however, we showed that activation and steady-state inactivation of recombinant Nav1.6 channels both irreversibly left-shift (up to −20 mV) in traumatized membrane (Wang et al 2009) as if their voltage sensors are responding to the increased bilayer disorder of traumatized (blebbed) membrane. In axonal membrane traumatized to various extents, this should smear out the window current range leftward between the normal range toward the resting potential range, effectively degrading a well-confined window conductance into a TTX-sensitive “Na+-leak”.To assess whether minor membrane trauma could lead to Na+ (and hence Ca2+) loading of axons, we model partially left-shifted Nav operation in a free-running human node of Ranvier. Included are Kv and Nav conductances (linear and electrodiffusion driving forces, respectively) and a Na/K pump, with [ion]s (and associated ENa and EK) in realistic-sized intra- and extracellular compartments changing due to net ion fluxes. Left-shifting a fraction of the Navs immediately triggers a damped action potential burst then a voltage plateau dominated by window current. If resting conductances are large enough, pumping restores the system for several minutes, then more bursting starts and more ENa rundown occurs.