Hostname: page-component-848d4c4894-cjp7w Total loading time: 0 Render date: 2024-06-17T19:31:42.489Z Has data issue: false hasContentIssue false

Microglia in development: linking brain wiring to brain environment

Published online by Cambridge University Press:  06 July 2012

Rosa C. Paolicelli
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy
Cornelius T. Gross*
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy
Correspondence should be addressed to: Cornelius T. Gross, Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Via Ramarini 32, 00015 Monterotondo, Italy email:


Microglia are enigmatic non-neuronal cells that infiltrate and take up residence in the brain during development and are thought to perform a surveillance function. An established literature has documented how microglia are activated by pathogenic stimuli and how they contribute to and resolve injuries to the brain. However, much less work has been aimed at understanding their function in the uninjured brain. A series of recent in vivo imaging studies shows that microglia in their resting state are highly motile and actively survey their neuronal surroundings. Furthermore, new data suggest that microglia in their resting state are able to phagocytose unwanted synapses and in this way contribute to synaptic pruning and maturation during development. Coupled with their exquisite sensitivity to pathogenic stimuli, these data suggest that microglia form a link that couples changes in brain environment to changes in brain wiring. Here we discuss this hypothesis and propose a model for the role of microglia during development in sculpting brain connectivity.

Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)



Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W. and Rossi, F.M. (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neuroscience 10, 15381543.CrossRefGoogle ScholarPubMed
Alliot, F., Godin, I. and Pessac, B. (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Research Development Brain Research 117, 145152.CrossRefGoogle ScholarPubMed
Biber, K., Neumann, H., Inoue, K. and Boddeke, H.W. (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends in Neurosciences 30, 596602.CrossRefGoogle ScholarPubMed
Bilbo, S.D., Barrientos, R.M., Eads, A.S., Northcutt, A., Watkins, L.R., Rudy, J.W. et al. (2008) Early-life infection leads to altered BDNF and IL-1beta mRNA expression in rat hippocampus following learning in adulthood. Brain Behavior Immunity 22, 451455.CrossRefGoogle ScholarPubMed
Bilbo, S.D., Biedenkapp, J.C., Der-Avakian, A., Watkins, L.R., Rudy, J.W. and Maier, S.F. (2005) Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. Journal of Neuroscience 25, 80008009.CrossRefGoogle ScholarPubMed
Bilbo, S.D., Rudy, J.W., Watkins, L.R. and Maier, S.F. (2006) A behavioural characterization of neonatal infection-facilitated memory impairment in adult rats. Behavioural Brain Research 169, 3947.CrossRefGoogle ScholarPubMed
Block, M.L., Zecca, L. and Hong, J.-S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8, 5769.CrossRefGoogle ScholarPubMed
Broderick, C., Duncan, L., Taylor, N. and Dick, A.D. (2000) IFN- and LPS mediatedIL-10-dependent suppression of retinal microglial activation. Investigative Ophthalmolgy and Visual Science 41, 26132622.Google ScholarPubMed
Brown, A.S. and Derkits, E.J. (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry 167, 261280.CrossRefGoogle ScholarPubMed
Buehler, M.R. (2011) A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder. Medical Hypotheses 76, 863870.CrossRefGoogle ScholarPubMed
Chan, W.Y., Kohsaka, S. and Rezaie, P. (2007) The origin and cell lineage of microglia: new concepts. Brain Research Reviews 53, 344354.CrossRefGoogle ScholarPubMed
Chang, Y.P., Fang, K.M., Lee, T.I. and Tzeng, S.F.J. (2006) Regulation of microglial activities by glial cell line derived neurotrophic factor. Cell Biochemistry 97, 501511.CrossRefGoogle ScholarPubMed
Chen, S.-K., Tvrdik, P., Peden, E., Cho, S., Wu, S., Spangrude, G. et al. (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775785.CrossRefGoogle ScholarPubMed
Ciaranello, A.-L. and Ciaranello, R.D. (1995) The neurobiology of infantile autism. Annual Review of Neuroscience 18, 101128.CrossRefGoogle ScholarPubMed
Cruz-Martin, A., Crespo, M. and Portera-Cailliau, C. (2010) Delayed stabilization of dendritic spines in fragile X mice. Journal of Neuroscience 30, 77937803.CrossRefGoogle ScholarPubMed
Cuadros, M.A., Martin, C., Coltey, P., Almendros, A. and Navascués, J. (1993) First appearance, distribution, and origin of macrophages in the early development of the avian central nervous system. Journal of Comparative Neurology 330, 113129.CrossRefGoogle ScholarPubMed
Dalmau, I., Finsen, B., Zimmer, J., González, B. and Castellano, B. (1998) Development of microglia in the postnatal rat hippocampus. Hippocampus 8, 458474.3.0.CO;2-N>CrossRefGoogle ScholarPubMed
Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S. et al. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 8, 752758.CrossRefGoogle ScholarPubMed
Del Rio-Hortega, P. (1932) Microglia. In Penfield, W. (ed.) Cytology and Cellular Pathology of the Nervous System. Hoeber, New York. pp. 481534.Google Scholar
Gilmore, J.H. and Jarskog, L.F. (1997) Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia. Schizophrenia Research 24, 365367.CrossRefGoogle ScholarPubMed
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S. et al. (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841845.CrossRefGoogle ScholarPubMed
Graeber, M.B. (2010) Changing face of microglia. Science 330, 783788.CrossRefGoogle ScholarPubMed
Hanisch, U.-K. and Kettenmann, H. (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience 10, 13871394.CrossRefGoogle ScholarPubMed
Herbomel, P., Thisse, B. and Thisse, C. (2001) Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process. Devlopmental Biology 238, 274288.CrossRefGoogle ScholarPubMed
Hristova, M., Cuthill, D., Zbarsky, V., Acosta-Saltos, A., Wallace, A., Blight, K. et al. (2010) Activation and deactivation of periventricular white matter phagocytes during postnatal mouse development. Glia 58, 1128.CrossRefGoogle ScholarPubMed
Jung, S., Aliberti, J., Graemmel, P., Sunshine, M.J., Kreutzberg, G.W., Sher, A. et al. (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green flourescent protein reporter gene insertion. Molecular Cellular Biology 20, 41064114.CrossRefGoogle Scholar
Kitamura, Y., Takata, K., Inden, M., Tsuchiya, D., Yanagisawa, D., Nakata, J. et al. (2004) Intracerebroventricular injection of microglia protects against focal brain ischemia. Journal of Pharmacological Sciences. 94, 203206.CrossRefGoogle ScholarPubMed
Koenigsknecht-Talboo, J. and Landreth, G.E. (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. Journal of Neuroscience 25, 82408249.CrossRefGoogle ScholarPubMed
Krabbe, G., Matyash, V., Pannasch, U., Mamer, L., Boddeke, H.W. and Kettenmann, H. (2012) Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behavior and Immunity 26, 419428.CrossRefGoogle ScholarPubMed
Lawson, L.J., Perry, V.H., Dri, P. and Gordon, S. (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151170.CrossRefGoogle ScholarPubMed
Lee, T.I., Yang, C.S., Fang, K.M. and Tzeng, S.F. (2009) Role of ciliary neurotrophic factor in microglial phagocytosis. Neurochemical Research 34, 109117.CrossRefGoogle ScholarPubMed
Ling, E.A., Kaur, C., Yick, T.Y. and Wong, W.C. (1990) Immunocytochemical localization of CR3 complement receptors with OX-42 in amoeboid microglia in postnatal rats. Anatomy and Embryology 182, 481486.CrossRefGoogle ScholarPubMed
Linnartz, B., Kopatz, J., Tenner, A.J. and Neumann, H. (2012) Sialic acid on the neuronal glycocalyx prevents complement c1 binding and complement receptor-3-mediated removal by microglia. Journal of Neuroscience 32, 946952.CrossRefGoogle ScholarPubMed
Lyck, L., Santamaria, I.D., Pakkenberg, B., Chemnitz, J., Schrøder, H.D., Finsen, B. et al. (2009) An empirical analysis of the precision of estimating the numbers of neurons and glia in human neocortex using a fractionator-design with sub-sampling. Journal of Neuroscience Methods 182, 143156.CrossRefGoogle ScholarPubMed
Mallat, M., Marín-Teva, J.L. and Chéret, C. (2005) Phagocytosis in the developing CNS: more than clearing the corpses. Current Opinion in Neurobiology 15, 101107.CrossRefGoogle ScholarPubMed
Marín-Teva, J.L., Dusart, I., Colin, C., Gervais, A., van Rooijen, N. and Mallat, M. (2004) Microglia promote the death of developing Purkinje cells. Neuron 41, 535547.CrossRefGoogle ScholarPubMed
McAlonan, G.M., Li, Q. and Cheung, C. (2010) The timing and specificity of prenatal immune risk factors for autism modeled in the mouse and relevance to schizophrenia. Neurosignals 18, 129139.CrossRefGoogle ScholarPubMed
Meyer, U., Feldon, J. and Dammann, O. (2011) Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatric Research 69, 26R33R.CrossRefGoogle ScholarPubMed
Meyer, U., Feldon, J. and Fatemi, S.H. (2009) In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neuroscience and Biobehavioral Reviews 33, 10611079.CrossRefGoogle ScholarPubMed
Meyer, U., Murray, P.J., Urwyler, A., Yee, B.K., Schedlowski, M. and Feldon, J. (2008) Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro inflammatory and IL-10-mediated anti-inflammatory signaling. Molecular Psychiatry 13, 208221.CrossRefGoogle ScholarPubMed
Meyer, U., Nyffeler, M., Engler, A., Urwyler, A., Schedlowski, M., Knuesel, I. et al. (2006) The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. Journal of Neuroscience 26, 47524762.CrossRefGoogle ScholarPubMed
Ming, G.L. and Song, H. (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687702.CrossRefGoogle ScholarPubMed
Mitrasinovic, O.M., Vincent, V.A., Simsek, D. and Murphy, G.M. Jr (2003) Macrophage colony stimulating factor promotes phagocytosis by murine microglia. Neuroscience Letters 344, 185188.CrossRefGoogle ScholarPubMed
Mody, M., Cao, Y., Cui, Z., Tay, K.-Y., Shyong, A., Shimizu, E. et al. (2001) Genome-wide gene expression profiles of the developing mouse hippocampus. Proceedings of the National Academy of Sciences of the U.S.A. 98, 88628867.CrossRefGoogle ScholarPubMed
Monje, M.L., Toda, H. and Palmer, T.D. (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 17601765.CrossRefGoogle ScholarPubMed
Mount, M.P., Lira, A., Grimes, D., Smith, P.D., Faucher, S., Slack, R. et al. (2007) Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. Journal of Neuroscience. 27, 33283337.CrossRefGoogle ScholarPubMed
Nagano, T., Kimura, S.H. and Takemura, M. (2010) Prostaglandin E2 reduces amyloid beta-induced phagocytosis in cultured rat microglia. Brain Research 1323, 1117.CrossRefGoogle ScholarPubMed
Nimmerjahn, A., Kirchhoff, F. and Helmchen, F. (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 13141318.CrossRefGoogle ScholarPubMed
Pan, X.D., Zhu, Y.G., Lin, N., Zhang, J., Ye, Q.Y., Huang, H.P. et al. (2011) Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease. Molecular Neurodegeneration 6, 45.CrossRefGoogle ScholarPubMed
Paolicelli, R.C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P. et al. (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 233, 14561458.CrossRefGoogle Scholar
Patterson, P.H. (2011) Maternal infection and immune involvement in autism. Trends in Molecular Medicine 17, 389394.CrossRefGoogle ScholarPubMed
Peri, F. and Nüsslein-Volhard, C. (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133, 916927.CrossRefGoogle ScholarPubMed
Pont-Lezica, L., Béchade, C., Belarif-Cantaut, Y., Pascual, O. and Bessis, A. (2011) Physiological roles of microglia during development. Journal of Neurochemistry 119, 901908.CrossRefGoogle ScholarPubMed
Ransohoff, R.M. and Cardona, A.E. (2010) The myeloid cells of the central nervous system parenchyma. Nature 468, 253262.CrossRefGoogle ScholarPubMed
Saijo, K. and Glass, C.K. (2011) Microglial cell origin and phenotypes in health and disease. Nature Reviews Immunology 11, 775787.CrossRefGoogle ScholarPubMed
Santos, A.M., Calvente, R., Tassi, M., Carrasco, M.-C., Martín-Oliva, D., Marín-Teva, J.L. et al. (2008) Embryonic and postnatal development of microglial cells in the mouse retina. Journal of Comparative Neurology 506, 224239.CrossRefGoogle ScholarPubMed
Schafer, D.P. and Stevens, B. (2010) Synapse elimination during development and disease: immune molecules take centre stage. Biochemical Society Transactions 38, 476481.CrossRefGoogle ScholarPubMed
Sierra, A., Encinas, J.M., Deudero, J.J.P., Chancey, J.H., Enikolopov, G., Overstreet-Wadiche, L.S. et al. (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483495.CrossRefGoogle ScholarPubMed
Smith, S.E., Li, J., Garbett, K., Mirnics, K. and Patterson, P.H. (2007) Maternal immune activation alters fetal brain development through interleukin-6. Journal of Neuroscience 27, 1069510702.CrossRefGoogle ScholarPubMed
Stevens, B., Allen, N.J., Vazquez, L.E., Howell, G.R., Christopherson, K.S., Nouri, N. et al. (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131, 11641178.CrossRefGoogle ScholarPubMed
Thomas, A., Gasque, P., Vaudry, D., Gonzalez, B. and Fontaine, M. (2000) Expression of a complete and functional complement system by human neuronal cells in vitro. International Immunology 12, 10151023.CrossRefGoogle ScholarPubMed
Tremblay, M.-È., Lowery, R.L. and Majewska, A.K. (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biology 8, e1000527.CrossRefGoogle ScholarPubMed
Verney, C., Monier, A., Fallet-Bianco, C. and Gressens, P. (2010) Early microglial colonization of the human forebrain and possible involvement in periventricular white-matter injury of preterm infants. Journal of Anatomy 217, 436448.CrossRefGoogle ScholarPubMed
Vuillermot, S., Joodmardi, E., Perlmann, T., Ove Ögren, S., Feldon, J. and Meyer, U. (2012) Prenatal immune activation interacts with genetic nurr1 deficiency in the development of attentional impairments. Journal of Neuroscience 32, 436451.CrossRefGoogle ScholarPubMed
Wake, H., Moorhouse, A.J., Jinno, S., Kohsaka, S. and Nabekura, J. (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. Journal of Neuroscience 29, 39743980.CrossRefGoogle ScholarPubMed
Wakselman, S., Béchade, C., Roumier, A., Bernard, D., Triller, A. and Bessis, A. (2008) Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. Journal of Neuroscience 28, 81388143.CrossRefGoogle ScholarPubMed
Walker, D.G., Kim, S.U. and McGeer, P.L. (1995) Complement and cytokine gene expression in cultured microglial derived from postmortem human brains. Journal of Neuroscience Research 40, 478493.CrossRefGoogle ScholarPubMed