The effects of pharmacological inhibition of M3R on myelination
Khaku, Zainab M.
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The importance of myelin is illustrated in demyelinating disease, such as Multiple Sclerosis (MS). In such diseases, the loss of myelin sheaths results in functional deficits due to conduction block and axonal damage. Successful remyelination, or generation of new myelin sheaths, is dependent on the recruitment, differentiation, and maturation of precursor cells to mature cells capable of repair. However this process is limited and becomes less effective over time (Franklin & Ffrench-Constant, 2008). To identify targets for pharmacological intervention, we performed gene expression analysis of human oligodendrocyte progenitor cells (hOPCs) isolated from fetal brain. This revealed high expression of muscarinic M3 receptor (M 3 R) mRNA, with expression greatest at the point of oligodendrocyte commitment. The primary goal of this study was to determine whether regulation of M 3 R can promote myelination by influencing oligodendrocyte fate and therefore act as a viable therapeutic target for human demyelinating diseases. We hypothesized that M 3 R signaling in OPCs regulates the timing and rate of oligodendrocyte differentiation in vivo and acts to delay oligodendrocyte maturation via a direct effect on OPCs. In order to test this hypothesis, we used an FDA-approved muscarinic receptor antagonist, solifenacin, on human and mouse OPCs. Results illustrated an increase in myelin basic protein (MBP) which indicates that receptor activity can modify cell differentiation. Additionally, there was improvement in physical function as seen by an increase in conductance in the auditory brainstem of the engrafted hypomyelinated shiverer/rag2 mouse. We then determined the cell-type specific expression pattern of M 3 R throughout development to identify what stage in the oligodendrocyte lineage M 3 R is expressed. Lastly, conditional NG2CreER and CNPCre M 3 R knockout mice were used to obtain a better understanding of the molecular mechanisms of the receptor. By identifying this particular receptor these data provides information that will be relevant in generating specific adjunct therapeutic strategies for human demyelinating diseases.