Neurotransmitter signalling to two types of oligodendrocyte precursor cell in remyelination

For nerve fibres in the brain and spinal cord (the central nervous system, or CNS) to work properly, and enable us to feel, move, talk, see, think etc., they need to be covered by a sheath called myelin. In many neurological diseases myelin is lost and nerve fibres cannot conduct impulses properly, and may even die. Just as a skin wound can heal, myelin injuries can be healed spontaneously by stem cells present in the CNS. However, this repair process, called remyelination, often fails. Scientists are therefore studying how CNS stem cells can be encouraged to heal myelin injury more efficiently. In this project we will determine the role of two distinct CNS stem cells that we have recently identified in remyelination.

When myelin is first produced in the developing brain the process is influenced by small molecules released from neurons, called neurotransmitters. However, it is unknown whether these neurotransmitters can influence remyelination. In this project we will study how remyelination by one or both types of stem cell is regulated by neurotransmitters. The results of this project will help in devising new remyelination therapies.

Demyelination has profound consequences for the efficiency of action potential conduction along axons, and for axonal integrity. In the CNS demyelination can be followed by a regenerative process called remyelination. However, in many myelin diseases (e.g. multiple sclerosis, trauma, stroke, cerebral palsy) remyelination is inadequate. Consequently, treatment of myelin diseases requires the development of remyelination-enhancing therapies, of which there are currently none. Remyelination is mediated by an endogenous population of stem/precursor cells called oligodendrocyte precursor cells (OPCs). We have recently shown that there are two populations of OPCs with distinct electrophysiological phenotypes: one type expresses voltage-gated sodium channels, fires action potentials and receives synaptic input, whereas the other type does not. At present it is not known whether both types of OPC become activated following demyelination and are able to differentiate into remyelinating oligodendrocytes. Furthermore, normal myelination has been shown to be influenced by axonal action potentials and neurotransmitter signalling, but at present there is no knowledge available regarding the effect of neurotransmitters on remyelination. This project will address the important questions of which OPC type should be targeted for remyelination-enhancing therapies, and whether modulation of neurotransmitter signalling could be used to enhance remyelination.