Upper and lower limb motor axons demonstrate differential excitability and accommodation to strong hyperpolarizing...

Length-dependent peripheral neuropathy typically involves the insidious onset of sensory loss in the lower limbs before later progressing proximally. Recent evidence proposes hyperpolarization-activated cyclic nucleotide-gated (HCN) channels as dysfunctional in rodent models of peripheral neuropathy, and therefore differential expression of HCN channels in the lower limbs was hypothesized as a pathophysiological mechanism accounting for the pattern of symptomatology within this study. We studied six healthy participants, using motor axon excitability including strong and long [-70% and -100% hyperpolarizing threshold electrotonus (TEh)] hyperpolarizing currents to preferably study HCN channel function from the median and tibial nerves from high (40%) and low (20%) threshold. This was recorded at normothermia (~32°C) and then repeated during hyperthermia (~40°C) as an artificial hyperpolarizing axon stress. Significant differences between recovery cycle, superexcitability, accommodation to small depolarizing currents, and alterations in late stages of the inward-rectifying currents of strongest (-70% and -100% TEh) currents were observed in the lower limbs during hyperthermia. We demonstrate differences in late I_H current flow, which implies higher expression of HCN channel isoforms. The findings also indicate their potential inference in the symptomatology of length-dependent peripheral neuropathies and may be a unique target for minimizing symptomatology and pathogenesis in acquired disease. NEW & NOTEWORTHY This study demonstrates nerve excitability differences between the upper and lower limbs during hyperthermia, an experimentally induced axonal stress. The findings indicate that there is differential expression of slow hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms between the upper and lower limbs, which was demonstrated through strong, long hyperpolarizing currents during hyperthermia. Such mechanisms may underlie postural control but render the lower limbs susceptible to dysfunction in disease states.