| Myelin formation is dependent on neuronal activity in both developing and aged CNS. Electrical stimulation (ESTIM) is being utilized in a variety of clinical and experimental applications to provide patterned activity in order to restore function and enhance repair following CNS injury or disease. However, the mechanisms by which therapeutic applications achieve recovery are not well understood. Previous work in mixed neural cultures has shown that neuronal activity promotes the secretion of soluble molecules, such as glutamate, ATP, and LIF, which act on the oligodendrocytes (OLs) to control OL biology. Our data suggests that ESTIM also acts in a pattern-dependent way to promote OL contact and myelination. Pre-treatment of dissociated dorsal root ganglia neurons (DRGs) with ESTIM prior to OL addition also enhances myelination, suggesting that ESTIM induces a lasting change that may be independent of soluble factors released from electrically active neurons. Furthermore, increased neuronal cAMP is both sufficient and necessary to promote ESTIM-enhanced myelination. We have identified the GPI-linked glycoprotein F3-contactin as a potential mediator of these results since ESTIM promotes F3-contactin mRNA and protein expression in a cAMP-dependent fashion 24 and 48 hr after ESTIM application. Furthermore, soluble F3-contactin promotes both OL differentiation and axo-OL contact, and knocking down F3-contactin expression reduces axo-glial contact and the effect of ESTIM. Altogether, these data are the first to show activity-dependent mechanisms that persists for several days to induce axo-glial contact. |
