Effect of modulating glutamate signaling on myelinating oligodendrocytes and their development—A study in the zebrafish model

Myelination is crucial for the development and maintenance of axonal integrity, especially fast axonal action potential conduction. There is increasing evidence that glutamate signaling and release through neuronal activity modulates the myelination process. In this study, we examine the effect of manipulating glutamate signaling on myelination of oligodendrocyte (OL) lineage cells and their development in zebrafish (zf). We use the “intensity‐based glutamate‐sensing fluorescent reporter” (iGluSnFR) in the zf model (both sexes) to address the hypothesis that glutamate is implicated in regulation of myelinating OLs. Our results show that glial iGluSnFR expression significantly reduces OL lineage cell number and the expression of myelin markers in larvae (zfl) and adult brains. The specific glutamate receptor agonist, L‐AP4, rescues this iGluSnFR effect by significantly increasing the expression of the myelin‐related genes, plp1b and mbpa, and enhances myelination in L‐AP4‐injected zfl compared to controls. Furthermore, we demonstrate that degrading glutamate using Glutamat‐Pyruvate Transaminase (GPT) or the blockade of glutamate reuptake by L‐trans‐pyrrolidine‐2,4‐dicarboxylate (PDC) significantly decreases myelin‐related genes and drastically declines myelination in brain ventricle‐injected zfl. Moreover, we found that myelin‐specific ClaudinK (CldnK) and 36K protein expression is significantly decreased in iGluSnFR‐expressing zfl and adult brains compared to controls. Taken together, this study confirms that glutamate signaling is directly required for the preservation of myelinating OLs and for the myelination process itself. These findings further suggest that glutamate signaling may provide novel targets to therapeutically boost remyelination in several demyelinating diseases of the CNS.