In injured neurons, “leaky” voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich membranes causes cytoplasmic Na+-loading and “Nav-CLS”, i.e., coupled left-(hyperpolarizing)-shift of Nav activation and availability. Metabolic injury of hippocampal neurons (epileptic discharge) results in comparable impairment: left-shifted activation and availability and hence left-shifted INa-window. A recent computation study revealed that CLS-based INa-window left-shift dissipates ion gradients and impairs excitability. Here, via dynamical analyses, we focus on sustained excitability patterns in mildly damaged nodes, in particular with more realistic Gaussian-distributed Nav-CLS to mimic “smeared” injury intensity. Since our interest is axons that might survive injury, pumps (sine qua non for live axons) are included. In some simulations, pump efficacy and system volumes are varied. Impacts of current noise inputs are also characterized. The diverse modes of spontaneous rhythmic activity evident in these scenarios are studied using bifurcation analysis. For “mild CLS injury”, a prominent feature is slow pump/leak-mediated EIon oscillations. These slow oscillations yield dynamic firing thresholds that underlie complex voltage STO and bursting behaviors. Thus, Nav-CLS, a biophysically justified mode of injury, in parallel with functioning pumps, robustly engenders an emergent slow process that triggers a plethora of pathological excitability patterns. This minimalist “device” could have physiological analogs. At first nodes of Ranvier and at nociceptors, e.g., localized lipid-tuning that modulated Nav midpoints could produce Nav-CLS, as could co-expression of appropriately differing Nav isoforms.
Nerve cells damaged by trauma, stroke, epilepsy, inflammatory conditions etc, have chronically leaky sodium channels that eventually kill. The usual job of sodium channels is to make brief voltage signals –action potentials– for long distance propagation. After sodium channels open to generate action potentials, sodium pumps work harder to re-establish the intracellular/extracellular sodium imbalance that is, literally, the neuron's battery for firing action potentials. Wherever tissue damage renders membranes overly fluid, we hypothesize, sodium channels become chronically leaky. Our experimental findings justify this. In fluidized membranes, sodium channel voltage sensors respond too easily, letting channels spend too much time open. Channels leak, pumps respond. By mathematical modeling, we show that in damaged channel-rich membranes the continual pump/leak counterplay would trigger the kinds of bizarre intermittent action potential bursts typical of injured neurons. Arising ectopically from injury regions, such neuropathic firing is unrelated to events in the external world. Drugs that can silence these deleterious electrical barrages without blocking healthy action potentials are needed. If fluidized membranes house the problematic leaky sodium channels, then drug side effects could be diminished by using drugs that accumulate most avidly into fluidized membranes, and that bind their targets with highest affinity there.