Investigating the role of muscarinic receptor subytpe 3 on OPC differentiation during remyelination
Welliver, Robert Ross
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In demyelinating diseases, such as multiple sclerosis, myelin sheaths and/or myelinating cells become damaged. Remyelination, an endogenous protective mechanism that restores myelin integrity, is critical for recovery from demyelinating insult (Jeffery and Blakemore 1997, Irvine and Blakemore 2008). Failure of this process results in axonal degeneration, which manifests in a variety of mild-to-severe cognitive, physical and psychological symptoms. Remyelination is dependent upon activation/proliferation, recruitment, differentiation and maturation of progenitor cells to become remyelination-competent cells. In the central nervous system, these progenitor cells are oligodendrocyte precursor cells, or OPCs. Modulators of OPC activation, recruitment and differentiation represent potential therapeutic targets for pharmacological enhancement of remyelination. Previous work in our lab (Abiraman, Pol et al. 2015) identified cholinergic muscarinic receptor subtype 3 (CHRM3, or M 3 R) in human OPCs as a possible target for manipulation of OPC fate. Several in vitro studies showed that M3R signaling modulates OPC commitment and differentiation. Subsequent studies in vivo demonstrated that M 3 R antagonism influences developmental myelination and functional repair mediated by xenografted human OPCs. Therefore, the primary goal of this study was to investigate the role of M3R antagonist treatment in a mouse model of demyelination. Using an FDA-approved muscarinic antagonist, solifenacin, we hypothesized that systemic muscarinic antagonist treatment would enhance OPC differentiation in demyelinated lesions. We observed increased density of PLP1+ oligodendrocytes at 14 days post-lesion when solifenacin treatment was initiated on day of lesion. This data indicates that M 3 R antagonist treatment increases OPC differentiation in demyelinated lesions. Preliminary mRNA expression analysis by RT-qPCR demonstrates the dynamic M 3 R expression during remyelination. Future studies will elucidate the effect of solifenacin on remyelination per se and on the cell autonomy of this effect. Taken together, these data suggest that M3R signaling may be useful in therapeutic modulation of OPC differentiation in demyelinating diseases.