Neuronal activity induces myelin voltage changes that reflect action potential dependent myelin potassium buffering

Vertebrate axons can be wrapped by myelin produced by oligodendrocytes. This cellular interaction ensures fast and accurate propagation of action potentials, but the physiology of the myelin sheath is almost completely unknown. To investigate the physiology of the myelin sheath, we implemented an imaging strategy that allowed optical measurements of myelin membrane voltage, with the aim to identify physiological changes of the myelin membrane during neuronal firing. We expressed the genetically encoded voltage indicator ASAP3 in mouse oligodendrocytes in vivo and subsequently investigated myelin physiology by optically measuring myelin membrane voltage. We found that myelin depolarizes during neuronal activity, which is blocked by inhibiting neuronal action potentials. Pharmacological and knock-out experiments of Kir4.1 showed that potassium uptake channels mediate action potential induced depolarization. Blocking myelin dependent potassium uptake and direct application of high potassium to identified axons induced axonal initiated and antidromic propagating action potentials. Our study shows that myelin is not an electrically passive insulator, but exhibits ion dynamics and its physiological response is fine tuned to neuronal activity. By facilitating potassium removal during action potentials, myelin supports high precision axonal firing. Genetically encoded sensors are thus a useful tool to study physiological properties of myelin, inaccessible by classical techniques. Highlights Optical imaging of myelin membrane potential Myelin sheaths exhibit depolarization in response to neuronal firing Depolarizations are partially mediated through Kir channels Potassium originates from axonal Kv channels