Neuregulin and BDNF Induce a Switch to NMDA Receptor-Dependent Myelination by Oligodendrocytes

Abstract

Neuregulin switches oligodendrocytes between two modes of myelination: from a neuronal activity–independent mode to a myelin-increasing, neuronal activity–dependent, mechanism that involves glutamate release and NMDA receptor activation.

Abstract

Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.

Author Summary

Myelination acts as an insulator for neurons and as such is essential for normal brain function, ensuring fast neuronal communication. Oligodendrocytes are the cells that wrap their membrane around nerve cell axons to form the myelin sheath that enables fast action potential propagation. However, what determines whether an individual axon becomes myelinated remains unknown. We show that there are two distinct modes of myelination: one that is independent of neuronal activity and the release of the neurotransmitter glutamate and another that depends on nerve cell action potentials releasing glutamate, which then activates a class of glutamate receptor (NMDA receptors) on oligodendrocyte lineage cells. We find that the protein neuregulin switches oligodendrocytes between these two modes of myelination; neuregulin increases oligodendrocyte lineage cells' sensitivity to glutamate by increasing the current flowing through their glutamate receptors. With neuregulin present, myelination is accelerated and increased. Blocking NMDA receptors reduces the amount of myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. We also demonstrate that remyelination after white matter damage (as occurs in diseases, such as spinal cord injury and multiple sclerosis) is NMDA receptor-dependent. These data help us understand the signalling that regulates myelination and suggest the possible involvement of neuregulin in schizophrenia and in remyelination after white matter damage.