Activity-dependent Ca2+ signalling is well established for somata and terminals of mammalian spinal motor neurons, but not for their axons. Imaging of an intra-axonally injected fluorescent [Ca2+] indicator revealed that during repetitive action potential stimulation, [Ca2+] elevations localized to nodal regions occurred in mouse motor axons from ventral roots, phrenic nerve and intramuscular branches. These [Ca2+] elevations (∼0.1 μm with stimulation at 50 Hz, 10 s) were blocked by removal of Ca2+ from the extracellular solution. Effects of pharmacological blockers indicated contributions from both T-type Ca2+ channels and reverse mode Na+/Ca2+ exchange (NCX). Acute disruption of paranodal myelin (by stretch or lysophosphatidylcholine) increased the stimulation-induced [Ca2+] elevations, which now included a prominent contribution from L-type Ca2+ channels. These results suggest that the peri-nodal axolemma of motor axons includes multiple pathways for stimulation-induced Ca2+ influx, some active in normally-myelinated axons (T-type channels, NCX), others active only when exposed by myelin disruption (L-type channels). The modest axoplasmic peri-nodal [Ca2+] elevations measured in intact motor axons might mediate local responses to axonal activation. The larger [Ca2+] elevations measured after myelin disruption might, over time, contribute to the axonal degeneration observed in peripheral demyelinating neuropathies.
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