Microglia contact cerebral vasculature through gaps between astrocyte endfeet

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The close spatial relationship between microglia and cerebral blood vessels implicates microglia in vascular development, homeostasis and disease. In this study we used the publicly available Cortical MM^3 electron microscopy dataset to systematically investigate microglial interactions with the vasculature. Our analysis revealed that approximately 20% of microglia formed direct contacts with blood vessels through gaps between adjacent astrocyte endfeet. We termed these contact points “plugs”. Plug-forming microglia exhibited closer proximity to blood vessels than non-plug forming microglia and formed multiple plugs, predominantly near the soma, ranging in surface area from ∼0.01 μm 2 to ∼15 μm 2 . Plugs were enriched at the venule end of the vascular tree and displayed a preference for contacting endothelial cells over pericytes at a ratio of 3:1. In summary, we provide novel insights into the ultrastructural relationship between microglia and the vasculature, laying a foundation for understanding how these contacts contribute to the functional cross-talk between microglia and cells of the vasculature in health and disease.

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  1. It was notable that 95% of microglial plugs covered <1 μm2 in surface area. However, 3.8% of382plugs were >2 μm2 and appeared to essentially take the place of astrocyte endfeet over large383stretches of the vasculature.

    This finding, and the one described in the results showing that a single microglia could form 17 plugs made me wonder whether there was anything specific to the microglial morphology itself that could be used to predict these outliers. Would an unbiased analysis of all 3D reconstructed microglia cluster those that formed particularly large or numerous plugs together? Might these cells have a specific morphology? The potentially transient nature of these plugs/contacts might preclude interesting or interpretable findings, but it could lead you to subgroups of microglia to pay attention to.

  2. coverage of vessels, which if true would likely change the number or size of microglial plugs471observed.59 However, the reviewers of that paper raised some important concerns about472their cryo-fixation method

    This question of differences in morphology depending on the type of fixation was lingering as I read the paper, so I'm happy you addressed it directly here. I wonder whether there are any publicly available cryo-fixed datasets (either the original eLife study that you cite or others) where microglia could be ID'ed, to compare with the results in this study.

  3. Microglia of the mouse visual cortex were identified within the publicly available Cortical82MM^3 dataset (https://www.microns-explorer.org/cortical-mm3)

    I'm a fan of using publicly available datasets to explore new science. Kudos on this interesting project. One thing I was wondering as I read the paper was how easy it was for you to use and navigate this dataset, since that can be a significant hurdle depending on the data type. Any comment on challenges, or what was made easy, by the organization of this dataset for your purposes could be really useful for others looking to analyze it.