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.