Validation of a conserved muscarinic receptor pathway that regulates human oligodendrocyte differentiation

Oligodendrocytes, the myelin producing cells in the nervous system, are destroyed in demyelinating diseases such as multiple sclerosis. Remyelination following demyelination restores rapid salutatory conduction of action potential and is capable of maintaining axonal integrity. Unfortunately, this process is not very efficient and thus it is necessary to develop therapies to promote remyelination.;Remyelination is being fairly extensively studied in rodents, however, human and rodent glia differ in response to environmental factors and express distinct gene expression profiles during development. Therefore, we have quantitatively analyzed whole genome expression profiles of three fractions of oligodendrocytes using CD140a and O4 antigens and compared these to similar mouse isolates (Cahoy et al., J. Neurosci. 28:264-278, 2008).The M 3 muscarinic acetylcholine receptor (CHRM3) was identified as the most significantly expressed receptor conserved between species. Muscarinic agonist treatment of CD140a+ OPCs was found to result in a specific and dose-dependent block of oligodendrocyte commitment. Furthermore, when human OPCs were co-cultured with fetal neurons, human OPCs were induced to differentiate as oligodendrocytes following M3 antagonist treatment. As CHRM3 was among a substantial number of transcripts conserved between species, we thus sought to determine whether muscarinic antagonist, solifenacin, treatment might influence oligodendrocyte differentiation in vivo. Treatment of mouse pups during the period of initial oligodendrocyte progenitor differentiation induced a large increase in area occupied by MBP+ myelin fibers in the corpus callosum at 9 days. Finally, we assessed whether antagonist treatment might similarly influence human OPC differentiation in vivo following transplantation into hypomyelinating shiverer/rag2 mice. Importantly, solifenacin administration led to a substantial increase in myelin basic protein MBP+ human CD140a+ OPCs at 8 weeks following transplantation indicating that muscarinic antagonists could modify human cell differentiation in vivo. We are therefore hopeful that M3 receptor antagonism will be a relevant clinical target for induced myelination.