Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Exp Neurol. 2016 Feb;276:41-50. doi: 10.1016/j.expneurol.2015.10.006. Epub 2015 Oct 26.
Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo-myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis.
有髓轴突在长距离内有效地传递信息。对向的髓鞘赋予有利的电学特性，但限制了轴突与细胞外环境的接触。因此，轴突的代谢支持可能需要特定的轴突-髓鞘通讯。在这里，我们探索了从轴突到髓鞘的活性依赖性谷氨酸介导的信号传递。使用双光子显微镜在体外成像视神经轴突电刺激引起的髓鞘 Ca(2+)变化。我们表明，视神经髓鞘通过 GluN2D 和 GluN3A 包含的 NMDA 受体介导的 Ca(2+)水平升高对轴突动作电位作出反应。谷氨酸以囊泡方式从轴突释放，该方式对破伤风毒素敏感。囊泡融合的 Ca(2+)来源是由轴突 Ca(2+)储存器上的 Ryanodine 受体提供的，由感知节间轴突质膜去极化的 L 型 Ca(2+)通道控制。GluN2D 和 GluN3A 亚基的基因缺失导致致密髓鞘的不稳定性增加。我们的结果支持轴突与其髓鞘之间存在新型突触，表明穿越动作电位可以向覆盖髓鞘发出信号的一种方式。这可能是轴突可以向伴生胶质细胞发出代谢支持信号或动态调节其髓鞘特性的重要生理机制。轴突-髓鞘突触可能有助于学习，而其紊乱可能在中枢神经系统疾病的病理生理学中发挥作用，例如精神分裂症，在人类中已经显示出有髓白质束的细微异常，或者在多发性硬化等明显脱髓鞘疾病中发挥作用。
