Length-dependent axonal degeneration typically occurs in axonal neuropathies. This “dying back” phenomenon occurs in the largest and longest axons. Because in these axons the demand for maintenance is highest and delivery of metabolites most challenging, impairment of metabolic processes essential for maintenance of axonal integrity is thought to explain this length-dependency. Moldovan et al. now elegantly demonstrate that electrophysiological axolemmal membrane characteristics may be partly explain susceptibility to axonal neuropathies. Using the Bostock “threshold tracking” methodology to measure membrane excitability, the authors discovered that, in normal human subjects and rats, nodal K+ slow outward rectifier conductance (GKsN) and the internodal hyperpolarisation-activated cyclic nucleotide-gated channels inward rectifier conductance (GH) are not normally distributed and exhibit a length-dependent gradient, leading to an increase in axonal cable capacitance with increasing distance. The authors conclude that this could contribute to length-dependent gradients in susceptibility to neuropathy.
by Prof. Peter Van den Bergh and Prof. Davide Pareyson
co-chairs of the EAN Scientific Panel on Peripheral Neuropathies
An axonal membrane excitability gradient could contribute to the length-dependent susceptibility to neuropathy
- Moldovan1, R. Arnold2, M. Rosberg1, S. Alvarez1, R. Morris2, C. Krarup3 1Neuroscience and Pharmacology, Copenhagen University, Copenhagen, Denmark, 2Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, Sydney, Australia, 3Clinical Neurophysiology, Rigshospitalet, Copenhagen, Denmark
Background and aims: In conditions of a neurotoxic insult involving the peripheral nerves, the resulting sensory-motor polyneuropathy is commonly length-dependent. When facing perturbations in membrane potential, the axonal excitability is maintained by an interplay between the nodal K+ slow outward rectifier conductance (GKsN) and the internodal hyperpolarisation-activated cyclic nucleotide- gated channels inward rectifier conductance (GH). The aim of this study was to investigate whether these rectifying conductances are distributed uniformly along the length of peripheral motor axons.
Methods: Multiple measures of motor nerve excitability by “threshold-tracking” were used to ascertain the voltage- dependent and passive cable axonal properties at different sites of stimulation along peripheral nerves in 20 healthy adult volunteers (median nerve at wrist and elbow and peroneal nerve) as well as in 15 adult female Long Evans rats under general anaesthesia (ulnar, tibial and caudal nerve – 2 sites). Interpretation of the excitability measures was carried out by optimising the parameters of the “Bostock” nodal-internodal myelinated motor axon mathematical model.
Results: Excitability measures differed considerably both between nerves and along the same nerve, especially in response to prolonged subthreshold depolarising and hyperpolarizing currents. In both human and rat there was an increase in GH, a decrease in GKsN and an increase in axonal cable capacitance CAX with increasing distance of the stimulation site from the spinal cord.
Conclusion: Our data suggest that there is a length- dependent gradient of the distribution of rectifying conductances required for the maintenance of membrane potential of peripheral nerves. This could contribute to length-dependent gradients in susceptibility to neuropathy.
Disclosure: Nothing to disclose