MYELIN PLASTICITY MEDIATED BY NMDA RECEPTORS CONTAINING GLUN3A SUBUNITS OLIGODENDROCYTE PROGENITOR CELLS

The myelin sheaths enwrapping axons are highly dynamic and can be remodeled through life by axonal activity and experience. “Myelin plasticity”, plays a key role in remodeling developing and adult neural circuits to support adaptive behavior or functional recovery upon injury. Yet the mechanisms are unknown. Here we show that NMDA receptors containing GluN3A subunits are expressed by oligodendrocyte progenitor cells (OPCs), where they localize at axon-OPC “synapse-like” contacts, and are essentially required for activity-
dependent myelin plasticity. Specifically, we find that GluN3A-lacking OPCs fail to differentiate to chemo-genetic stimulation of callosal axons. Similar deficits were observed when:selective GluN3A deletion from OPCs was driven by Sox10-Cre or inducible PDGFRα-CreERT2 lines; OPC responses were triggered using natural paradigms that elicit myelin plasticity, includingexercise or fine motor training in the Erasmus Ladder. At the behavioral level, OPC-selective GluN3A deletion severely impaired adaptive motor learning and interfered with remote memory consolidation. Our study identifies the first known molecular sensor for myelin plasticity, opening avenues to boost myelin plasticity based on re-expressing GluN3A or modulating downstream signaling pathways.