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Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week
Open accessAbstract
During postnatal development, microglia, CNS resident innate immune cells, are essential for synaptic pruning, neuronal apoptosis and remodeling. During this period microglia undergo morphological and phenotypic transformations; however, little is known about how microglial number and density is regulated during postnatal CNS development. We found that after an initial increase during the first 14 postnatal days, microglial numbers in mouse brain began declining in the third postnatal week and were reduced by 50% by 6weeks of age; these "adult" levels were maintained until at least 9months of age. Microglial CD11b levels increased, whereas CD45 and ER-MP58 declined between P10 and adulthood, consistent with a maturing microglial phenotype. Our data indicate that both increased microglial apoptosis and a decreased proliferative capacity contribute to the developmental reduction in microglial numbers. We found no correlation between developmental reductions in microglial numbers and brain mRNA levels of Cd200, Cx3Cl1, M-Csf or Il-34. We tested the ability of M-Csf-overexpression, a key growth factor promoting microglial proliferation and survival, to prevent microglial loss in the third postnatal week. Mice overexpressing M-Csf in astrocytes had higher numbers of microglia at all ages tested. However, the developmental decline in microglial numbers still occurred, suggesting that chronically elevated M-CSF is unable to overcome the developmental decrease in microglial numbers. Whereas the identity of the factor(s) regulating microglial number and density during development remains to be determined, it is likely that microglia respond to a "maturation" signal since the reduction in microglial numbers coincides with CNS maturation.
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“Microglia in the first two postnatal weeks are highly proliferative (Nikodemova et al., 2015).”
From Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing (2019) · cites this paper as Nikodemova et al., 2015
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BackgroundA Comparative Biology of Microglia Across Species
Sharma, K. P., Bisht, K., & Eyo, U. B. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.652748 · Cited by 46
“In addition to their complex morphology, microglia are the most morphologically dynamic cells of the vertebrate brain (Davalos et al., 2005; Nimmerjahn, 2012).”
BackgroundEyo, U. B., Miner, S. A., Weiner, J. A., & Dailey, M. E. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.11.009 · Cited by 39
“(2015), http://dx.doi.org/10.1016/j.bbi.201 development in the mouse (Nikodemova et al., 2015).”
InfluentialThe multifaceted roles of embryonic microglia in the developing brain
Hattori, Y. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.988952 · Cited by 44
The dual function of microglial polarization and its treatment targets in ischemic stroke
Mo, Y., Xu, W., Fu, K., Chen, H., Wen, J., Huang, Q., Guo, F., Mo, L., & Yan, J. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.921705 · Cited by 39
“A decrease in the rate of proliferation accompanied by an increase in apoptosis results in a decrease in the overall number of microglia, and mature microglia maintain their numbers in the CNS by self-renewal (23, 24).”
BackgroundStables, J., Green, E. K., Sehgal, A., Patkar, O. L., Keshvari, S., Taylor, I., Ashcroft, M. E., Grabert, K., Wollscheid-Lengeling, E., Szymkowiak, S., et al. (2022) · Development · doi:10.1242/dev.200237 · Cited by 39
de Soysa, Y., Therrien, M., Walker, A. C., & Stevens, B. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101651 · Cited by 34
Loss of microglial EED impairs synapse density, learning, and memory
Wang, Y.-Y., Deng, Y.-S., Dai, S.-K., Mi, T.-W., Li, R.-Y., Liu, P.-P., Liu, C., He, B.-D., He, X.-C., Du, H.-Z., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01576-w · Cited by 32
“The microglial population in the healthy brain is reduced by 50% and maintained in adulthood [45].”
BackgroundAlbertini, G., D’Andrea, I., Druart, M., Béchade, C., Nieves-Rivera, N., Etienne, F., Magueresse, C. L., Rebsam, A., Heck, N., Maroteaux, L., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02048-5 · Cited by 37
“During postnatal development, microglia also undergo a transition from amoeboid to rami fi ed [20, 21], in a sex-dependent manner [28].”
BackgroundOxytocin and microglia in the development of social behaviour
Gonzalez, A. M., & Hammock, E. A. D. (2022) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2021.0059 · Cited by 32
Single-cell atlas reveals meningeal leukocyte heterogeneity in the developing mouse brainPreprint
Zelco, A., Börjesson, V., de Kanter, J. K., Lebrero‐Fernández, C., Lauschke, V. M., Rocha‐Ferreira, E., Nilsson, G., Nair, S., Svedin, P., Bemark, M., et al. (2021) · Genes & Development · doi:10.1101/gad.348190.120 · Cited by 34
“(2019) In addition, subcluster 2 also showed enriched proliferative processes as seen previously for microglia in the first 2 wk of life (Nikodemova et al. 2015), and subcluster 13 seems to be involved in neurogenesis and nervous system development.”
BackgroundMicroglia in the Brain Tumor Microenvironment
Cole, A. P., Hoffmeyer, E., Chetty, S. L., Cruz, J. C., Hamrick, F. A., Youssef, O. A., Cheshier, S. H., & Mitra, S. S. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-49270-0_11 · Cited by 30
A critical postnatal period of heightened vulnerability to lipopolysaccharide
Rourke, K. S., Mayer, C. A., & MacFarlane, P. M. (2016) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2016.06.003 · Cited by 26
Microglial regulation of satiety and cognition
Luca, S. N. D., Miller, A. A., Sominsky, L., & Spencer, S. J. (2020) · Journal of Neuroendocrinology · doi:10.1111/jne.12838 · Cited by 28
Establishment of tissue-resident immune populations in the fetus
Feyaerts, D., Urbschat, C., Gaudilliere, B. L., & Stelzer, I. A. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00931-x · Cited by 30
“From rodent studies, it is known that their numbers contract in postnatal week 3 and subsequently stabilize to adult levels after week 4 [145, 146].”
BackgroundOsborne, B. F., Turano, A., Caulfield, J. I., & Schwarz, J. M. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.10.044 · Cited by 30
Morphological evidence indicates a role for microglia in shaping the PCOS‐like brain
Sati, A., Prescott, M., Holland, S., Jasoni, C. L., Desroziers, E., & Campbell, R. E. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12999 · Cited by 27
Astrocytes and microglia in the coordination of CNS development and homeostasis
Lopez‐Ortiz, A. O., & Eyo, U. B. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.16006 · Cited by 32
“However, microglial numbers peak in the second week of post-natal development (Kim et al., 2015; Nikodemova et al., 2015) and are trimmed by the third week (Nikodemova et al., 2015; Paolicelli et al., 2011), and although astrocytes have not been documented to be instrumental in the reduction of…”
Riquier, A. J., & Sollars, S. I. (2019) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2019.100010 · Cited by 26
Modulatory effects of mesenchymal stem cells on microglia in ischemic stroke
Hao, L., Yang, Y., Xu, X., Guo, X., & QunLing, Z. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2022.1073958 · Cited by 25
“There are more microglia in the hippocampus and the olfactory bulb and fewer microglia in the fiber bundle (25).”
BackgroundLoewen, S. M., Chavesa, A. M., Murray, C. J., Traetta, M. E., Burns, S. E., Pekarik, K. H., & Tremblay, M. (2023) · Developmental Neuroscience · doi:10.1159/000530185 · Cited by 28
Nitric oxide signaling inhibits microglia proliferation by activation of protein kinase-G
Maksoud, M., Tellios, V., Xiang, Y., & Lu, W.-Y. (2019) · Nitric Oxide · doi:10.1016/j.niox.2019.11.005 · Cited by 24
First Encounters: Effects of the Microbiota on Neonatal Brain Development
Gars, A., Ronczkowski, N. M., Chassaing, B., Castillo‐Ruiz, A., & Forger, N. G. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.682505 · Cited by 25
Solarz, A., Majcher‐Maślanka, I., Kryst, J., & Chocyk, A. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.11.005 · Cited by 24
Developmental functions of microglia: Impact of psychosocial and physiological early life stress
Smail, M. A., & Lenz, K. M. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110084 · Cited by 24
“The hippocampus (HPC), cortex (CTX), and amygdala (AMY) are some of the first regions”
The Complementary Role of Morphology in Understanding Microglial Functional Heterogeneity
Godeanu, S., & Cătălin, B. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26083811 · Cited by 22
“This balance can vary over time, with an increase in apoptosis and a decrease in proliferation being noted immediately postnatally [43].”
Sex- and Development-Dependent Responses of Rat Microglia to Pro- and Anti-inflammatory Stimulation
Lively, S. S., Wong, R., Lam, D., & Schlichter, L. C. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00433 · Cited by 20
“Increasingly, it is recognized that sex can profoundly influence both the susceptibility and response to disease (Ober et al., 2008; Regitz-Zagrosek, 2012).”
BackgroundSingle-cell RNA sequencing identifies hippocampal microglial dysregulation in diet-induced obesity
Henn, R. E., Guo, K., Elzinga, S. E., Noureldein, M. H., Mendelson, F. E., Hayes, J. M., Rigan, D. M., Savelieff, M. G., Hur, J., & Feldman, E. L. (2023) · iScience · doi:10.1016/j.isci.2023.106164 · Cited by 18
Microglia in pediatric brain tumors: The missing link to successful immunotherapy
du Chatinier, A., Velilla, I. Q., Meel, M. H., Hoving, E. W., Hulleman, E., & Metselaar, D. S. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101246 · Cited by 22
“5 8 However, the role of developmental microglia in pediatric brain tumors is not well understood, despite a noteworthy increase in interest in this topic.”
BackgroundLewen, A., Ta, T., Cesetti, T., Hollnagel, J., Papageorgiou, I. E., Chausse, B., & Kann, O. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24689 · Cited by 18
“2.7 | Recordings of local field potential and [K+]o For electrophysiological recordings, the intact Biopore™ membrane carrying slice cultures was inserted into the recording chamber (Kann et al., 2011; Papageorgiou et al., 2016).”
BackgroundMethodInfluentialClinical and experimental aspects of breathing modulation by inflammation
Peña‐Ortega, F. (2018) · Autonomic Neuroscience · doi:10.1016/j.autneu.2018.11.002 · Cited by 21
Boyle, B. R., Melli, S. E., Altreche, R. S., Padron, Z. M., Yousufzai, F. A. K., Kim, S., Vasquez, M. D., Carone, D. M., Carone, B. R., & Soto, I. (2020) · Development · doi:10.1242/dev.189019 · Cited by 18
“Interestingly, a reduced number of cerebellar granule cells and reductions in cerebellar lobule size at the end of postnatal development have been found in Npc1−/− mice (Nusca et al., 2014).”
BackgroundSkowronski, A. A., LeDuc, C. A., Foo, K. S., Goffer, Y., Burnett, L. C., Egli, D. M., & Leibel, R. L. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aax6629 · Cited by 18
Daura, E., Tegelberg, S., Hakala, P., Lehesjoki, A., & Joensuu, T. H. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1069122 · Cited by 15
“In wt cerebellum, the percentage of dividing microglia decreased from approximately 16% at P14 to 1% at P21 and at P30, in line with previous findings (Nikodemova et al., 2015).”
BackgroundResultThe Potential Impact of the Gut Microbiota on Neonatal Brain Development and Adverse Health Outcomes
Tzitiridou‐Chatzopoulou, M., Kountouras, J., & Ζουρνατζίδου, Γ. (2024) · Children · doi:10.3390/children11050552 · Cited by 16
“Additionally, these microglia experience alterations in their physical structure and gene expression [1].”
BackgroundRiquier, A. J., & Sollars, S. I. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.04.037 · Cited by 16
“…determine if the time course of microglia presence in the developing rat rNTS is similar to that observed in other brain areas (Alliot et al., 1999; Nikodemova et al., 2015), and to determine whether microglia density differences correspond to known periods of CT terminal field pruning (Sollars et…”
Metadata
- Authors
- Nikodemova, M., Kimyon, R. S., De, I., Small, A. L., Collier, L. S., & Watters, J. J.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Watters, Jyoti J.
- Venue
- Journal of Neuroimmunology
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 278
- Pages
- 280-288
- ISSN
- 0165-5728 (ISSN-L)
- PMC
- PMC4297717
- OpenAlex
- W1974031039
- Cited by
- 192
- References
- 56
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 12 · 2023: 20 · 2022: 16 · 2021: 31 · 2020: 24 · 2019: 17 · 2018: 11 · 2017: 11 · 2016: 11 · 2015: 4
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroimmunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (NS049033, HL111598)
- Goldhirsh Foundation
- UW Madison Graduate School
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, postnatal brain development, microglial apoptosis, microglial proliferation, macrophage colony-stimulating factor, microglial maturation, CD11b, CD45, CD200, fractalkine, IL-34, microglial phenotype
- MeSH terms
- Aging, Animals, Animals, Newborn, Brain, Female, Flow Cytometry, Male, Mice, Inbred ICR, Cytokines, Apoptosis, Microglia, CD11b Antigen, Cell Proliferation, Mice
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