Abstract
In multiple sclerosis, exacerbation of symptoms with rising body temperature is associated with impulse conduction failure. The mechanism is not fully understood. Remarkably, normal optic nerve axons also show temperature dependent effects, with a fall in excitability with warming. Here we show two properties of optic nerve axons, accommodation and inward rectification (Ih), respond to temperature changes in a manner consistent with a temperature dependent membrane potential. As we could find no evidence for the functional expression of KV7.2 in the axons, using the K+ channel blocker tetraethylammonium ions, we suggest this may explain the membrane potential lability. In order to understand how the axonal membrane potential may show temperature dependence, we have developed a hypothesis involving the electroneutral movement of Na+ ions across the axon membrane, that increases with increasing temperature with an appropriate Q10. Part, but probably not all, of the electroneutral Na+ movement is eliminated by removing extracellular Cl− or exposure to bumetanide, consistent with the involvement of the transporter NKCC1. Numerical simulation suggests a change in membrane potential of − 15–20 mV mimics altering temperature between room and physiological in the largest axons.
Highlights
In multiple sclerosis, exacerbation of symptoms with rising body temperature is associated with impulse conduction failure
Recovery cycles are known to be a sensitive measure of axonal function, because the properties of the axons modifying the measurement of the cycle are critically dependent on membrane potential, including for example the kinetics of N a+ channel inactivation and the internodal conductance (e.g.4,10)
In the present experiments we found that the effect on threshold at 15 min drug exposure was substantially reduced at room temperature, on average, from that found at 32–35 °C, this reduction in change was not statistically significant (Fig. 3b)
Summary
Exacerbation of symptoms with rising body temperature is associated with impulse conduction failure. Under circumstances where there are an abundance of operable Na+ channels, the changes in threshold parallel changes in membrane potential, and such TE data can be obtained from humans, non-invasively, and have been used to study the functional properties of axonal voltage-gated ion channels in patients, including those altered by mutation (e.g.8). By recording such threshold changes, studies in both human and rodent peripheral nerve have revealed otherwise inaccessible information about the state of the axons, and how this state can change, for example with changes in temperature or vascular perfusion
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