The role of GLT-1 signaling in oligodendrocytes during development and myelin repair

The differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes (OLGs) requires an increase in the complexity of process morphology, alterations in membrane trafficking, and the production of myelin proteins. Branching and process extension have already been shown to follow glutamate signaling through OLG-expressed excitatory amino acid transporters (EAATs), mostly via GLT-1. It is of note that glutamate homeostasis often goes awry in multiple sclerosis (MS), the main demyelinating disease in humans. Thus, we have sought to gain an understanding of the role that GLT-1 plays under the myelination and remyelination conditions that arise during natural development of OLGs and during MS, respectively. Our data presented here show that in males, the conditional knockout of Glt-1 during development results in lower GLT-1 surface expression, a reduced frequency of myelinated fibers, and diminished g-ratios in smaller diameter fibers. Additionally, both male and female primary OLGs treated with D-Aspartate demonstrate increased process morphology and branching. Treatment with D-Aspartate also results in the downregulation of Rhob, which has been shown to lessen the rate of endocytosis and cause the mobilization of stored vesicles, steps that are crucial to OLG differentiation. Further initial results combining the Glt-1 cKO with cuprizone feeding to induce demyelination/remyelination have pointed to a potentially protective effect of the cKO. Overall, these data suggest activation of GLT-1 results in a signaling cascade that leads to the downregulation of Rhob and the subsequent maturation of OLGs