Fig. 8. Activity-mediated model of axon–OL metabolic coupling.

The scheme shows a working model in which axon–OL communication and metabolic coupling in the white matter are controlled by K⁺ and Kir4.1-mediated signaling. Fast axonal spiking induces a rapid increase in OL [Ca²⁺] and glycolysis. OLs primarily detect axonal activity through elevated [K⁺]_ext and activation of Kir4.1 channels. This K⁺-mediated signaling facilitates the supply of lactate (or pyruvate) to axons. Apart from regulating acute metabolic coupling, oligodendroglial Kir4.1 adjusts the myelinic levels of MCT1 and GLUT1. In addition to lactate, OLs might supply axons with glucose and/or modulate axonal glucose uptake at the nodes of Ranvier. Oligodendroglial K⁺ homeostasis also influences axonal glycolysis, which is likely critical for preserving axonal integrity through various glucose metabolism-dependent processes, such as antioxidant protection through the pentose phosphate pathway (PPP), biosynthesis of molecules required for structure and function, regulation of the redox state, and vesicular transport. The potential contribution of astrocytes as a source of (glycogen-derived) lactate (or pyruvate) for axons is not depicted in this scheme, pending future studies. Nav, voltage-gated sodium channel; Kv, voltage-gated potassium channel.