The Glial Coupling in the Developing Brain: Astrocytes, Oligodendrocytes and Myelin Formation

Myelination in the developing brain emerges from a dynamic interplay among oligodendrocytes, astrocytes, neurons, vascular components, and immune cells. Although astrocyte–oligodendrocyte interactions are increasingly recognized as critical for myelin formation, maintenance, and metabolic homeostasis, their developmental organization remains incompletely understood, particularly in extremely preterm infants, in whom mature astrocytic functions are not yet fully established. This narrative review examines how oligodendrocyte maturation and white-matter metabolism may be supported across development and how perinatal insults can perturb this evolving cellular cooperation. Evidence from experimental, neuropathological, metabolic, and neuroimaging studies indicates that oligodendrocytes are not passive recipients of astrocytic support but active metabolic, signaling, and immunological partners whose functions evolve alongside astroglial maturation. In the immature white matter, this relationship is further shaped by neuronal activity, vascular substrate delivery, inflammatory signaling, and the intrinsic vulnerability of pre-oligodendrocytes. Hypoxia–ischemia, oxidative stress, iron dyshomeostasis, ferroptosis, and glycemic instability may therefore interfere with multiple components of this developing network. Human and experimental evidence from perinatal white-matter injury is particularly informative, showing the coexistence of reactive astrogliosis, pre-oligodendrocyte injury and maturation arrest, and subsequent impairment of myelination. Quantitative neuroimaging, radiomics, proteomics, and lipidomics provide complementary observational scales through which these processes may be investigated, although imaging markers of myelin remain biologically non-specific. Taken together, the available evidence does not support a single cellular substitute for mature astrocytic function. Rather, oligodendrocyte maturation appears to depend on a developmentally changing division of metabolic, homeostatic, and signaling labour across multiple cellular compartments. We propose that glial coupling itself should therefore be considered a developmentally constructed process whose disruption may contribute to white-matter vulnerability in the preterm brain.