Preventing production of new oligodendrocytes impairs remyelination and sustains behavioural deficits after demyelination

Abstract

Damage to oligodendrocytes (OLs) and myelin sheaths (demyelination) has been shown to be associated with numerous neurological and psychiatric disorders. Remyelination is a rare and reliable regenerative response that occurs in the central nervous system (CNS). It is generally believed that OL progenitor cells (OPCs) are the cell source to generate new OLs to remyelinate the demyelinated axons. However, several recent studies have argued that pre-existing mature OLs that survive within the demyelinated area are responsible for remyelination. Here, by conditional knock-out (KO) of a transcription factor gene that is essential for OPC differentiation, namely myelin regulatory factor (Myrf), to block the production of adult new OLs and examined its effect on remyelination after cuprizone (CPZ)-induced demyelination. We found that OPCs specific Myrf cKO mice show dramatic impairment in remyelination after 4 weeks of recovery from 5 weeks of CPZ diet and they leave over significant behavioral deficits such as anxiety-like behavior, decreased motor skills, and impaired memory compared to control mice that have recovered for the same time. Our data support the idea that OPCs are the major cell sources for myelin regeneration, suggesting that targeting the activation of OPCs and promoting their differentiation to boost new OLs production is critical for therapeutic intervention for demyelinating diseases such as multiple sclerosis (MS).