From synapse to sheath: how OPCs couple neural activity to adaptive myelination and behavioral plasticity

Oligodendrocyte precursor cells (OPCs) are abundant progenitor cells in the central nervous system. Unlike mature oligodendrocytes, OPCs form functional synapses with neurons and respond to both glutamatergic and GABAergic signals. Glutamate activates calcium-permeable AMPA receptors on OPCs, generating local Ca²⁺ signals that regulate myelin sheath formation and stabilization. In parallel, GABAergic signaling modulates OPC proliferation and differentiation through both calcium-dependent and transcriptional mechanisms. Activity-dependent myelination driven by OPCs contributes directly to neural circuit plasticity and behavioral adaptation, including motor learning, spatial memory, fear extinction, and social experience-dependent brain development. Disruption of the OPC-synapse-myelin axis impairs remyelination and circuit function, contributing to neurological and psychiatric disorders such as multiple sclerosis, schizophrenia, and PTSD. In this review, we critically examine neuron-OPC communication across four interconnected levels: synaptic signaling, cellular fate regulation, myelin plasticity, and behavior. We highlight key limitations in the current evidence, including controversies over the functional role of OPC synapses in the adult brain, unclear mechanisms underlying myelin plasticity, and the largely correlative nature of human neuroimaging data. We argue that the field must move beyond descriptive observations toward rigorous mechanistic studies of causality, with particular attention to region- and cell-type-specific heterogeneity.