Abstract
Paranodal myelin damage is observed in white matter injury. However the culprit for such damage remains unknown. By coherent anti-Stokes Raman scattering imaging of myelin sheath in fresh tissues with sub-micron resolution, we observed significant paranodal myelin splitting and retraction following glutamate application both ex vivo and in vivo. Multimodal multiphoton imaging further showed that glutamate application broke axo-glial junctions and exposed juxtaparanodal K+ channels, resulting in axonal conduction deficit that was demonstrated by compound action potential measurements. The use of 4-aminopyridine, a broad-spectrum K+ channel blocker, effectively recovered both the amplitude and width of compound action potentials. Using CARS imaging as a quantitative readout of nodal length to diameter ratio, the same kind of paranodal myelin retraction was observed with applications of Ca2+ ionophore A23187. Moreover, exclusion of Ca2+ from the medium or application of calpain inhibitor abolished paranodal myelin retraction during glutamate exposure. Examinations of glutamate receptor agonists and antagonists further showed that the paranodal myelin damage was mediated by NMDA and kainate receptors. These results suggest that an increased level of glutamate in diseased white matter could impair paranodal myelin through receptor-mediated Ca2+ overloading and subsequent calpain activation.
Highlights
White matter of the central nervous system (CNS) is enriched in myelinated axons which are critical for reliable and efficient action potential conduction
coherent anti-Stokes Raman scattering (CARS) imaging reveals paranodal myelin splitting and retraction induced by glutamate The response of paranodal myelin to glutamate application was visualized on a laser-scanning CARS microscope
Myelin degradation around the node following 102 (20 mM) with glutamate (1 mM) glutamate application was monitored in real time
Summary
White matter of the central nervous system (CNS) is enriched in myelinated axons which are critical for reliable and efficient action potential conduction. The action potential is generated at nodes of Ranvier and propagates via saltatory conduction. Adjacent to the nodes are paranodes where axolemma and the lateral borders of myelin sheath are connected through the adhesion junctions. The integrity of paranodal domains is vital to fast action potential conduction along myelinated axons. Irreversible injury to white matter [1] leads to severe functional loss of the CNS in neurological disorders including stroke [2], multiple sclerosis (MS) [3], and spinal cord trauma [4]. Howell et al observed the disruption of adhesion junctions within and adjacent to actively demyelinating white matter lesions in MS tissues [7]. The culprit responsible for such paranodal myelin injury remains elusive to date
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