High-Frequency Microdomain Ca²⁺ Transients and Waves during Early Myelin Internode Remodeling

Ensheathment of axons by myelin is a highly complex and multi-cellular process. Cytosolic calcium (Ca²⁺) changes in the myelin sheath have been implicated in myelin synthesis, but the source of this Ca²⁺ and the role of neuronal activity is not well understood. Using one-photon Ca²⁺ imaging, we investigated myelin sheath formation in the mouse somatosensory cortex and found a high rate of spontaneous microdomain Ca²⁺ transients and large-amplitude Ca²⁺ waves propagating along the internode. The frequency of Ca²⁺ transients and waves rapidly declines with maturation and reactivates during remyelination. Unexpectedly, myelin microdomain Ca²⁺ transients occur independent of neuronal action potential generation or network activity but are nearly completely abolished when the mitochondrial permeability transition pores are blocked. These findings are supported by the discovery of mitochondria organelles in non-compacted myelin. Together, the results suggest that myelin microdomain Ca²⁺ signals are cell-autonomously driven by high activity of mitochondria during myelin remodeling.