glutamate excitotoxicity inflicts paranodal myelin splitting and retraction谷氨酸会造成paranodal髓分裂和收缩.pdfVIP

Glutamate Excitotoxicity Inflicts Paranodal Myelin Splitting and Retraction 1 2 1 1,2 1,3 Yan Fu , Wenjing Sun , Yunzhou Shi , Riyi Shi *, Ji-Xin Cheng * 1 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America, 2 Department of Basic Medical Sciences and Center for Paralysis Research, Purdue University, West Lafayette, Indiana, United States of America, 3 Department of Chemistry, Purdue University, West Lafayette, Indiana, United States of America 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 NM