Abstract
Microglia are the brain's resident immune cells with a tremendous capacity to autonomously self-renew. Because microglial self-renewal has largely been studied using static tools, its mechanisms and kinetics are not well understood. Using chronic in vivo two-photon imaging in awake mice, we confirm that cortical microglia show limited turnover and migration under basal conditions. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of remaining microglia, in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly born microglia resemble mature microglia within days of repopulation, although morphological maturation is different in newly born microglia in P2Y12 knock out mice. Our work suggests that microglia rapidly locally and that newly born microglia do not recapitulate the slow maturation seen in development but instead take on mature roles in the CNS.
Highlights
Microglia are the resident tissue macrophages of the brain (Crotti and Ransohoff, 2016; Ginhoux et al, 2010) with a developmental origin that is distinct from other macrophages (Ginhoux et al, 2010)
Because a growing body of literature suggests that microglia behave differently under anesthesia (Li et al, 2012; Stowell et al, 2019; Sun et al, 2019) we wanted to capture the dynamics of microglia in the absence of anesthesia to avoid potentially inducing long-term alteration in microglial movement and turnover during repopulation
When surveillance was normalized to the original microglial morphology to account for the loss of microglia with depletion, we found that individual microglia surveilled their territory in the same manner throughout control, depletion and repopulation conditions (Figure 6i)
Summary
Microglia are the resident tissue macrophages of the brain (Crotti and Ransohoff, 2016; Ginhoux et al, 2010) with a developmental origin that is distinct from other macrophages (Ginhoux et al, 2010). Motile microglial processes remodel, prune, and define neuronal circuits and establish transient physical contacts with synapses that influence neuronal circuits during early development and adulthood (Miyamoto, 2016; Paolicelli, 2011; Parkhurst et al, 2013; Schafer, 2010; Sipe et al, 2016; Tremblay et al, 2010) In addition to their many homeostatic roles in physiological brain function, these cells are traditionally known as a first line of defense in neuropathology and participate in responses to injury, infection, and neurological disease. Chronic microglial activation is associated with a number of neurodegenerative and neurodevelopmental diseases such as Alzheimer’s Disease, Schizophrenia and Autism Spectrum Disorder (Bilbo et al, 2018; Kettenmann, 2011; Spittau, 2017)
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