Myelin pruning by microglia during development

Myelinis a lipid rich membrane produced by oligodendrocytesin the central nervous system. During development, oligodendrocyteprecursor cells find their target axons and start to wrap their processes around axons, thereby creating a multilayered insulating sheath. Those sheaths are regularly distributed along the axon with small, intersecting gaps called Nodesof Ranvier. This insulation results in increase in signaling conduction velocity. Furthermore, recent publications suggest that myelinis a dynamic structure that can adapt to environmental changes. I investigated the epigenetic control of oligodendrocytesduring motor skill learning, since it was suggested in literature, that myelinis necessary for complex learning. Mice were subjected to a complex running wheel and the corpus callosum, a region with high myelindensity, were collected for batch isolation of tissue specific methylated DNA immunoprecipitation(Bits-meDIP), before and several days after complex learning. Thereby i could not identify changes of differentially methylated regionsor genes. Myelinplasticity is also visible during development, where the formation of the myelin sheathis accompanied by myelinoutfoldings, which are normally linked to disease pathology. Here, I investigated the ultrastructural changes of myelinby 2D and 3D electron microscopy during optic nerve development. Thus, I could see degenerated myelindebris additional to outfoldings in wild type optic nerves. Interestingly, degenerated myelinwas not only seen in the extracellular space, but also still attached to otherwise normal looking myelin sheath. Additionally, microgliawere found to be associated with myelinoutfoldings and phagocytose degenerated myelin. This phenomenon has already been described for demyelinating diseasemodels, however not yet for normal myelindevelopment. Activation of microgliaduring that time seemed to be dependent on triggering receptor on myeloid cells 2 ( TREM2) signaling, since TREM2deficient animals showed less expression of the activation markers. Despite that RNA sequencing of white and grey matter microgliaat 14 and 60 days after birth did not show an increase in genes usually expressed in disease-associated microglia(DAM) – a microglial subtype which arises in a Trem2-dependent manner. Pathway analysisshowed that P14 microgliain cortex and corpus callosumexpressed genes related to extracellular matrix interaction, cytokine signaling, focal adhesion and protein digestion, when compared to P60 microglia. Hence, redundant myelinduring development is unlikely to be sufficient to trigger severe disease related gene expression.