Persistent alterations in active and passive electrical membrane properties of regenerated nerve fibers of man and mice

Abstract

Excitability of regenerated fibers remains impaired due to changes in both passive cable properties and alterations in the voltage-dependent membrane function. These abnormalities were studied by mathematical modeling in human regenerated nerves and experimental studies in mice. In three adult male patients with surgically repaired complete injuries of peripheral nerves of the arm 22 months-26 years prior to investigation, deviation of excitability measures was explained by a hyperpolarizing shift in the resting membrane potential and an increase in the passive 'Barrett and Barrett' conductance (GBB) bridging the nodal and internodal compartments. These changes were associated with an increase in the 'fast' K(+) conductance and the inward rectifier conductance (GH). Similar changes were found in regenerated mouse tibial motor axons at 1 month after a sciatic crush lesion. During the first 5 months of regeneration, GH showed partial recovery, which paralleled that in GBB. The internodal length remained one-third of normal. Excitability abnormalities could be reversed by the energy-dependent Na(+)/K(+) pump blocker ouabain resulting in membrane depolarization. Stressing the Na(+) pumping system during a strenuous activity protocol triggered partial Wallerian degeneration in regenerated nerves but not in control nerves from age-matched mice. The current data suggest that the nodal voltage-gated ion channel machinery is restored in regenerated axons, although the electrical separation from the internodal compartment remains compromised. Due to the persistent increase in number of nodes, the increased activity-dependent Na(+) influx could lead to hyperactivity of the Na(+)/K(+) pump resulting in membrane hyperpolarization and neurotoxic energy insufficiency during strenuous activity.

Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle

“…This matter, could in part be resolved, by performing nerve conduction velocity studies in both motor and sensory hindlimb nerves (i.e. tibial and sural nerve branches) since these are routinely performed in humans as well as in mice with suspected neuropathies [41]. …”

Burning pain: axonal dysfunction in erythromelalgia

“…65 Alterations in passive cable properties (myelin thickness and internodal length) may also change membrane potential or ion channel conductances, for example, shorter internodes in regenerated nerve and an increased number of nodes provide a greater intra-axonal Na + load to drive the Na + /K + pump. 58 This concept is unlikely as latency and conduction velocities were maintained and mathematical modeling did not support this as the most plausible explanation.…”

Altered axonal excitability properties in facial palsy

“…Long‐term studies of regenerated axons in a cat model demonstrated a tendency for depolarizing threshold electrotonus to return toward normal while abnormalities in hyperpolarizing threshold electrotonus persisted . Further exploration of this discrepancy suggested that the combination of structural shortening of internodal segments and overactivity of outwardly rectifying fast potassium currents may be the underlying cause …”

“…Nevertheless, the changes that were recorded may potentially reflect alterations in surviving as well as regenerated axons, and thus longitudinal studies will be required to definitively establish the exact contribution of each fiber type to the excitability changes noted in this study. Previous studies have shown that axonal excitability abnormalities in regenerating axons after Wallerian degeneration may persist for a prolonged period after the initial insult, 11,13 and these changes have been attributed to altered fiber diameter, shortened internodal length, altered resting membrane potential, and altered rectification properties. 14 Of note, there were no differences in excitability parameters between patients with greater vs. lower clinical severity of disease, as measured by the House-Brackmann score.…”

“…15 Further exploration of this discrepancy suggested that the combination of structural shortening of internodal segments and overactivity of outwardly rectifying fast potassium currents may be the underlying cause. 13,14 From a clinical perspective, the manifestations of facial palsy encompass varying degrees of weakness, spasm, involuntary movement, synkinesis, parasympathetic dysfunction (excessive or reduced tearing/ salivation), and sensory symptoms, such as pain, tightness, and fatigue. 1,2,16 Given this heterogeneity of clinical symptoms and the diversity of known causes of facial palsy, it is highly likely that more than one pathophysiological mechanism is at play.…”