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bioRxiv · 10.1101/2020.05.25.110908

A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature

Mondo, E.·Becker, S. C.·Kautzman, A. G.·Schifferer, M.·Baer, C. E.·Chen, J.·Huang, E. J.·Simons, M.·Schafer, D. P.
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Abstract

Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared to older ages and the timing of these associations are dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the prenatal human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages contact vascular areas void of astrocyte endfeet and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted upon the arrival of astrocyte endfeet when juxtavascular microglia then establish a long-term, stable contact with the vasculature. SIGNIFICANCE STATEMENTWe report the first extensive analysis of juxtavascular microglia in the healthy, developing and adult brain. Live imaging revealed that juxtavascular microglia within the cortex are highly motile and migrate along vessels as they are colonizing cortical regions. Using confocal, expansion, super-resolution, and electron microscopy, we determined that microglia associate with the vasculature at all ages in areas lacking full coverage astrocyte endfoot coverage and motility of juxtavascular microglia ceases as astrocyte endfeet more fully ensheath the vasculature. Our data lay the fundamental groundwork to investigate microglia-astrocyte crosstalk and juxtavascular microglial function in the healthy and diseased brain. They further provide a potential vascular-dependent mechanism by which microglia colonize the brain to later regulate neural circuit development.

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Mondo, E., Becker, S. C., Kautzman, A. G., Schifferer, M., Baer, C. E., Chen, J., Huang, E. J., Simons, M., Schafer, D. P.. 2020-05-25. A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature. https://doi.org/10.1101/2020.05.25.110908

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