Promoting myelination of regenerating axons for vision restoration

Abstract/Project Summary Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Demyelination associated with CNS trauma or diseases such as multiple sclerosis (MS) and glaucoma contributes significantly to behavioral deficits. Despite tremendous progress in understanding regulatory mechanisms of myelination, there are no pro-myelination treatments in the clinical setting. In our recent studies, using optic nerve/tract injury models, we discovered that injured axons could regenerate following intervention to elevate the regenerative ability of retinal ganglion cells (RGCs), yet these regenerated axons fail to be myelinated. Further, we showed that oligodendrocyte precursor cells (OPCs) do proliferate but fail to differentiate and mature into myelinating oligodendrocytes in response to ONC. With these unique models, we further demonstrated that blockade of muscarinic receptor 1 (M1R, or Chrm1) or GPR17 promoted OPC differentiation while depleting activated microglia facilitated the maturation or survival of newly formed oligodendrocytes. Thus, at least two overarching mechanisms contribute to the observed myelination failure: OPC intrinsic mechanisms preventing OPC differentiation, and microglia-relevant factors inhibiting the formation of mature oligodendrocytes by unknown mechanism(s). Importantly, treatments acting on these mechanisms promoted de novo myelination of regenerated axons and point to potential translatable pro- myelination strategies. In this application, following up with these initial findings, we will investigate the following questions: how do M1R and GPR17 regulate OPC differentiation? Do they work within the same signaling pathway(s)? How do activated microglia affect oligodendrocytes? Does treatment-induced de novo myelination improve behavioral outcome(s)? We expect that our studies will inform the mechanisms and therapeutic potential of myelination regeneration and visual restoration.