Coupled left-shift of Nav channels: modeling the Na+-loading and dysfunctional excitability of damaged axons

Abstract

Injury to neural tissue renders voltage-gated Na⁺ (Nav) channels leaky. Even mild axonal trauma initiates Na⁺-loading, leading to secondary Ca²⁺-loading and white matter degeneration. The nodal isoform is Nav1.6 and for Nav1.6-expressing HEK-cells, traumatic whole cell stretch causes an immediate tetrodotoxin-sensitive Na⁺-leak. In stretch-damaged oocyte patches, Nav1.6 current undergoes damage-intensity dependent hyperpolarizing- (left-) shifts, but whether left-shift underlies injured-axon Nav-leak is uncertain. Nav1.6 inactivation (availability) is kinetically limited by (coupled to) Nav activation, yielding coupled left-shift (CLS) of the two processes: CLS should move the steady-state Nav1.6 "window conductance" closer to typical firing thresholds. Here we simulated excitability and ion homeostasis in free-running nodes of Ranvier to assess if hallmark injured-axon behaviors--Na⁺-loading, ectopic excitation, propagation block--would occur with Nav-CLS. Intact/traumatized axolemma ratios were varied, and for some simulations Na/K pumps were included, with varied in/outside volumes. We simulated saltatory propagation with one mid-axon node variously traumatized. While dissipating the [Na⁺] gradient and hyperactivating the Na/K pump, Nav-CLS generated neuropathic pain-like ectopic bursts. Depending on CLS magnitude, fraction of Nav channels affected, and pump intensity, tonic or burst firing or nodal inexcitability occurred, with [Na⁺] and [K⁺] fluctuating. Severe CLS-induced inexcitability did not preclude Na⁺-loading; in fact, the steady-state Na⁺-leaks elicited large pump currents. At a mid-axon node, mild CLS perturbed normal anterograde propagation, and severe CLS blocked saltatory propagation. These results suggest that in damaged excitable cells, Nav-CLS could initiate cellular deterioration with attendant hyper- or hypo-excitability. Healthy-cell versions of Nav-CLS, however, could contribute to physiological rhythmic firing.

A computational model coupling mechanics and electrophysiology in spinal cord injury

“…This Na v (and in this model, K v ) leak has been rationalized by a hyperpolarizing shift (or left-shift) of transient current operational range (Wang et al 2009) in the conductance of the ion channel. Boucher et al (2012) proposed to capture this stretchinduced alteration by left-shifting the potential for Na v channels' activation and inactivation variables in the damaged part of the nodal axolemma. Despite the fact that such blebbing should a priori affect equally all types of ion channels, previous attempts to consider the leak of K v have not been fully pursued (Boucher et al 2012).…”

“…Boucher et al (2012) proposed to capture this stretchinduced alteration by left-shifting the potential for Na v channels' activation and inactivation variables in the damaged part of the nodal axolemma. Despite the fact that such blebbing should a priori affect equally all types of ion channels, previous attempts to consider the leak of K v have not been fully pursued (Boucher et al 2012). It has actually been suggested that the observed extracellular K + accumulation in post-traumatic rat hippocampal slices would be due to glial activity and not neuronal leak (D'Ambrosio et al 1999).…”

“…The modeling approach of Boucher et al (2012) involves the consideration of additional "left-shifted" m and h (see Table 2) calculated by increasing the potential V in a m , «h, An and jSh by a value related to the degree of damage. These left shifted m and h are then weighed-averaged with their healthy counterparts to obtain the factor multiplying C?Na, see Table 2.…”

“…Conversely, recent work building on the observation of "leaky" voltage-gated sodium ion channel after trauma (Wang et al 2009) has proposed a model of the resulting hyperpolarization-(left-)shifts of the ion channel current (Boucher et al 2012). This model successfully reproduces the effect of the trauma-induced blebbing 1 of a membrane patch on the electrophysiological properties of this patch.…”

“…The approach is multiscale by nature, defining mechanical properties at the axon level, while linking the electrophysiological properties of the corresponding membrane in the NRs or IRs to the deformation and damage of the overall axon. As such, the intrinsically heterogeneous microscopAxonal blebbing-or beading-consists of a series of undulating swellings at the NRs (Ochs et al 1994;Markvin et al 1999) leading to a loss of adhesion of the lipid bilayer to the underlying cortical axoplasm (Boucher et al 2012). ical mechanical and electrophysiological properties of the axonal components are homogenized at the mesoscale. Such approach, already widely used in the mechanical description of many types of materials [e.g., composite materials (Wu et al 2013)] benefits from a lower computational cost and thus allow for simulations of coupled multiscale phenomena currently unavailable to mechanical models defined solely at the microscale.…”