The Neurochemical Landscape of Oligodendrocyte Physiology: From Myelination to Metabolic and Synaptic Modulation

ABSTRACT Oligodendrocytes, traditionally recognized for their role in axonal myelination, are increasingly appreciated as metabolically dynamic and functionally diverse cells integral to central nervous system (CNS) homeostasis. This review delineates the evolving neurochemical landscape of oligodendrocyte physiology, emphasizing their roles beyond myelin production. We explore key processes including lipid metabolism, metabolic coupling with neurons, ion buffering, neurotransmitter signaling, and synaptic modulation. Oligodendrocytes preferentially utilize aerobic glycolysis and support axonal energy metabolism via the export of lactate and phosphocreatine, maintaining ATP levels even in the absence of mitochondria within the myelin sheath. Their capacity for regional and transcriptional heterogeneity allows adaptive responses to local microenvironments and neuronal activity. Lipid biosynthesis and storage mechanisms are intricately regulated through mTORC1, SREBPs, and lipophagy, enabling rapid membrane expansion, and structural integrity during myelination. Furthermore, oligodendrocytes modulate the periaxonal milieu via potassium buffering, pH regulation, and osmotic balance, primarily through Kir channels, carbonic anhydrases, and aquaporins. They also express a wide array of neurotransmitter receptors, enabling bidirectional communication with neurons and activity‐dependent modulation of maturation and plasticity. Intracellular signaling pathways such as PI3K/Akt/mTOR, MAPK/ERK, and Wnt/β‐catenin orchestrate the integration of metabolic and transcriptional programs. Collectively, these findings redefine oligodendrocytes as active participants in CNS physiology, contributing to neuronal health, circuit plasticity, and responses to injury or disease. image