Characterizing newly repopulated microglia in the adult mouse: impacts on animal behavior, cell morphology, and neuroinflammation
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Microglia are the primary immune cell in the brain and are postulated to play important roles outside of immunity. Administration of the dual colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor, PLX3397, to adult mice results in the elimination of ~99% of microglia, which remain eliminated for as long as treatment continues. Upon removal of the inhibitor, microglia rapidly repopulate the entire adult brain, stemming from a central nervous system (CNS) resident progenitor cell. Using this method of microglial elimination and repopulation, the role of microglia in both healthy and diseased states can be explored. Here, we examine the responsiveness of newly repopulated microglia to an inflammatory stimulus, as well as determine the impact of these cells on behavior, cognition, and neuroinflammation. Two month-old wild-type mice were placed on either control or PLX3397 diet for 21 d to eliminate microglia. PLX3397 diet was then removed in a subset of animals to allow microglia to repopulate and behavioral testing conducted beginning at 14 d repopulation. Finally, inflammatory profiling of the microglia-repopulated brain in response to lipopolysaccharide (LPS; 0.25 mg/kg) or phosphate buffered saline (PBS) was determined 21 d after inhibitor removal using quantitative real time polymerase chain reaction (RT-PCR), as well as detailed analyses of microglial morphologies. We find mice with repopulated microglia to perform similarly to controls by measures of behavior, cognition, and motor function. Compared to control/resident microglia, repopulated microglia had larger cell bodies and less complex branching in their processes, which resolved over time after inhibitor removal. Inflammatory profiling revealed that the mRNA gene expression of repopulated microglia was similar to normal resident microglia and that these new cells appear functional and responsive to LPS. Overall, these data demonstrate that newly repopulated microglia function similarly to the original resident microglia without any apparent adverse effects in healthy adult mice.
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In PLEX ablated/repopulated mice, EGFP+Iba1+ cells were abundant throughout analyzed basal ganglia nuclei, similar to repopulation dynamics reported in other brain regions.
“EGFP+Iba1+ cells were once again abundant throughout analyzed BG nuclei, similar to repopulation dynamics reported in other brain regions (Elmore et al., 2015)”
From Local cues establish and maintain region-specific phenotypes of basal ganglia microglia (2017) · cites this paper as Elmore et al., 2015
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Microglia Are Irrelevant for Neuronal Degeneration and Axon Regeneration after Acute Injury
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Microglia Are Critical in Host Defense against Prion Disease
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Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy
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Microglia as Therapeutic Target for Radiation-Induced Brain Injury
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Immune cell modulation of oligodendrocyte lineage cells
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Mitigation of helium irradiation-induced brain injury by microglia depletion
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Circulating Pro-Inflammatory Exosomes Worsen Stroke Outcomes in Aging
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Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease
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- Authors
- Elmore, M. R. P., Lee, R. J., West, B. L., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Plexxikon (United States) (US)
- Corresponding author
- Green, Kim N.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-04-07
- Volume
- 10
- Issue
- 4
- Pages
- e0122912
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4388515
- OpenAlex
- W2169700519
- Cited by
- 228
- References
- 73
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 19 · 2023: 19 · 2022: 23 · 2021: 32 · 2020: 26 · 2019: 28 · 2018: 23 · 2017: 18 · 2016: 6 · 2015: 4
- FWCI
- 9.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Plexxikon
- National Institute on Aging (T32AG000096)
- National Institute of Neurological Disorders and Stroke (R01NS083801)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- microglia, microglial repopulation, PLX3397, CSF1R inhibition, lipopolysaccharide response, neuroinflammation, microglial morphology, cognitive function, motor function, brain immune cells
- MeSH terms
- Animals, Brain, Cells, Cultured, Central Nervous System Diseases, Cognition, Female, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Motor Activity, Nerve Regeneration, Microglia, Maze Learning, Rotarod Performance Test, Cell Shape
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