Ih contributes to increased motoneuron excitability in restless legs syndrome

Key points

Restless legs patients complain about sensory and motor symptoms leading to sleep disturbances. Symptoms include painful sensations, urge to move and involuntary leg movements. The responsible mechanisms of restless legs syndrome are still not known, but current studies indicate an increased neuronal network excitability. Reflex studies indicate the involvement of spinal structures. Peripheral mechanisms have not been investigated so far. Here, we provide evidence of increased HCN channel‐mediated inward rectification in motor axons. The excitability of sensory axons was not changed. We conclude that in restless legs syndrome increased HCN current in motoneurons may play a pathophysiological role, and that these channels could represent a valuable target for pharmaceutical intervention.

Abstract

Restless legs syndrome is a sensorimotor network disorder. So far, the responsible pathophysiological mechanisms are poorly understood. Here, we provide evidence that the excitability of peripheral motoneurons contributes to the pathophysiology of restless legs syndrome. In vivo excitability studies on motor and sensory axons of the median nerve were performed on patients with idiopathic restless legs syndrome (iRLS) who were not currently on treatment. The iRLS patients had greater accommodation in motor but not sensory axons to long‐lasting hyperpolarization than age‐matched healthy subjects, indicating greater inward rectification in iRLS. The most reasonable explanation is that HCN channels open at less hyperpolarized membrane potentials, a view supported by mathematical modelling. The half‐activation potential for HCN [hyperpolarization‐activated cyclic nucleotide‐gated] channels (Bq) was the single best parameter that accounted for the difference between normal controls and iRLS data. A 6‐mV depolarization of Bq reduced the discrepancy between the normal control model and the iRLS data by 92.1%

Taken together, our results suggest for the first time an increase in excitability of motor units in iRLS which could enhance the likelihood of leg movements. The abnormal axonal properties are consistent with other findings that the peripheral system is part of the network involved in iRLS.

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