Activity-dependent structural plasticity of myelinated axons tunes their excitability

<jats:title>ABSTRACT</jats:title> <jats:p> Myelinated axons are classically viewed as stable cables of fixed geometry. We show here that a brief subthreshold stimulation of single nodes in mouse dorsal column axons drives a rapid, lasting structural change: the stimulated axons shrink locally along the internode segments adjacent to the node, to about 70% of their diameter within a few seconds, while neighbouring glia swell to fill the space, sparing the node, paranode and more distant internodes. The thinned axon becomes markedly more excitable for hours, by an amount cable theory predicts from its shorter internodal length constant rather than from active currents that tend to decay over long periods. Using a grease-gap signal that reports the axial-conductance change, we find the axon thinning requires under-myelin Kv1 channels, Na/K-ATPase pumps, bicarbonate, and altered pH, consistent with a regenerative periaxonal potassium build-up that osmotically compresses the axon and swells glia, as previously proposed for physiological high-frequency firing. We present evidence that this mechanism may contribute to the long-lasting clinical benefits of spinal cord stimulation. Axonal GABA <jats:sub>A</jats:sub> receptor activation reproduces and occludes the plasticity induced by stimulation, indicating that they share a common underlying mechanism. Activity-dependent axon thinning thus enables potent physiologically relevant long term control of conduction, with potential clinical applications. </jats:p>