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Microglia in development: linking brain wiring to brain environment

  • Rosa C. Paolicelli (a1) and Cornelius T. Gross (a1)

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.

Corresponding author
Correspondence should be addressed to: Cornelius T. Gross, Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Via Ramarini 32, 00015 Monterotondo, Italy email:
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B. Ajami , J.L. Bennett , C. Krieger , W. Tetzlaff and F.M. Rossi (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neuroscience 10, 15381543.

F. Alliot , I. Godin and B. Pessac (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Research Development Brain Research 117, 145152.

K. Biber , H. Neumann , K. Inoue and H.W. Boddeke (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends in Neurosciences 30, 596602.

S.D. Bilbo , R.M. Barrientos , A.S. Eads , A. Northcutt , L.R. Watkins , J.W. Rudy (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.

S.D. Bilbo , J.C. Biedenkapp , A. Der-Avakian , L.R. Watkins , J.W. Rudy and S.F. Maier (2005) Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. Journal of Neuroscience 25, 80008009.

S.D. Bilbo , J.W. Rudy , L.R. Watkins and S.F. Maier (2006) A behavioural characterization of neonatal infection-facilitated memory impairment in adult rats. Behavioural Brain Research 169, 3947.

M.L. Block , L. Zecca and J.-S. Hong (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8, 5769.

A.S. Brown and E.J. Derkits (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry 167, 261280.

M.R. Buehler (2011) A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder. Medical Hypotheses 76, 863870.

W.Y. Chan , S. Kohsaka and P. Rezaie (2007) The origin and cell lineage of microglia: new concepts. Brain Research Reviews 53, 344354.

Y.P. Chang , K.M. Fang , T.I. Lee and S.F.J. Tzeng (2006) Regulation of microglial activities by glial cell line derived neurotrophic factor. Cell Biochemistry 97, 501511.

A.-L. Ciaranello and R.D. Ciaranello (1995) The neurobiology of infantile autism. Annual Review of Neuroscience 18, 101128.

S.-K. Chen , P. Tvrdik , E. Peden , S. Cho , S. Wu , G. Spangrude (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775785.

M.A. Cuadros , C. Martin , P. Coltey , A. Almendros and J. Navascués (1993) First appearance, distribution, and origin of macrophages in the early development of the avian central nervous system. Journal of Comparative Neurology 330, 113129.

I. Dalmau , B. Finsen , J. Zimmer , B. González and B. Castellano (1998) Development of microglia in the postnatal rat hippocampus. Hippocampus 8, 458474.

D. Davalos , J. Grutzendler , G. Yang , J.V. Kim , Y. Zuo , S. Jung (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 8, 752758.

J.H. Gilmore and L.F. Jarskog (1997) Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia. Schizophrenia Research 24, 365367.

F. Ginhoux , M. Greter , M. Leboeuf , S. Nandi , P. See , S. Gokhan (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841845.

M.B. Graeber (2010) Changing face of microglia. Science 330, 783788.

U.-K. Hanisch and H. Kettenmann (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience 10, 13871394.

P. Herbomel , B. Thisse and C. Thisse (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.

M. Hristova , D. Cuthill , V. Zbarsky , A. Acosta-Saltos , A. Wallace , K. Blight (2010) Activation and deactivation of periventricular white matter phagocytes during postnatal mouse development. Glia 58, 1128.

Y. Kitamura , K. Takata , M. Inden , D. Tsuchiya , D. Yanagisawa , J. Nakata (2004) Intracerebroventricular injection of microglia protects against focal brain ischemia. Journal of Pharmacological Sciences. 94, 203206.

J. Koenigsknecht-Talboo and G.E. Landreth (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. Journal of Neuroscience 25, 82408249.

G. Krabbe , V. Matyash , U. Pannasch , L. Mamer , H.W. Boddeke and H. Kettenmann (2012) Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behavior and Immunity 26, 419428.

L.J. Lawson , V.H. Perry , P. Dri and S. Gordon (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151170.

T.I. Lee , C.S. Yang , K.M. Fang and S.F. Tzeng (2009) Role of ciliary neurotrophic factor in microglial phagocytosis. Neurochemical Research 34, 109117.

E.A. Ling , C. Kaur , T.Y. Yick and W.C. Wong (1990) Immunocytochemical localization of CR3 complement receptors with OX-42 in amoeboid microglia in postnatal rats. Anatomy and Embryology 182, 481486.

B. Linnartz , J. Kopatz , A.J. Tenner and H. Neumann (2012) Sialic acid on the neuronal glycocalyx prevents complement c1 binding and complement receptor-3-mediated removal by microglia. Journal of Neuroscience 32, 946952.

L. Lyck , I.D. Santamaria , B. Pakkenberg , J. Chemnitz , H.D. Schrøder , B. Finsen (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.

M. Mallat , J.L. Marín-Teva and C. Chéret (2005) Phagocytosis in the developing CNS: more than clearing the corpses. Current Opinion in Neurobiology 15, 101107.

J.L. Marín-Teva , I. Dusart , C. Colin , A. Gervais , N. van Rooijen and M. Mallat (2004) Microglia promote the death of developing Purkinje cells. Neuron 41, 535547.

G.M. McAlonan , Q. Li and C. Cheung (2010) The timing and specificity of prenatal immune risk factors for autism modeled in the mouse and relevance to schizophrenia. Neurosignals 18, 129139.

U. Meyer , J. Feldon and O. Dammann (2011) Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatric Research 69, 26R33R.

U. Meyer , J. Feldon and S.H. Fatemi (2009) In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neuroscience and Biobehavioral Reviews 33, 10611079.

U. Meyer , P.J. Murray , A. Urwyler , B.K. Yee , M. Schedlowski and J. Feldon (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.

U. Meyer , M. Nyffeler , A. Engler , A. Urwyler , M. Schedlowski , I. Knuesel (2006) The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. Journal of Neuroscience 26, 47524762.

G.L. Ming and H. Song (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687702.

O.M. Mitrasinovic , V.A. Vincent , D. Simsek and G.M. Murphy Jr (2003) Macrophage colony stimulating factor promotes phagocytosis by murine microglia. Neuroscience Letters 344, 185188.

M.L. Monje , H. Toda and T.D. Palmer (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 17601765.

M.P. Mount , A. Lira , D. Grimes , P.D. Smith , S. Faucher , R. Slack (2007) Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. Journal of Neuroscience. 27, 33283337.

T. Nagano , S.H. Kimura and M. Takemura (2010) Prostaglandin E2 reduces amyloid beta-induced phagocytosis in cultured rat microglia. Brain Research 1323, 1117.

A. Nimmerjahn , F. Kirchhoff and F. Helmchen (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 13141318.

X.D. Pan , Y.G. Zhu , N. Lin , J. Zhang , Q.Y. Ye , H.P. Huang (2011) Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease. Molecular Neurodegeneration 6, 45.

P.H. Patterson (2011) Maternal infection and immune involvement in autism. Trends in Molecular Medicine 17, 389394.

F. Peri and C. Nüsslein-Volhard (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133, 916927.

L. Pont-Lezica , C. Béchade , Y. Belarif-Cantaut , O. Pascual and A. Bessis (2011) Physiological roles of microglia during development. Journal of Neurochemistry 119, 901908.

R.M. Ransohoff and A.E. Cardona (2010) The myeloid cells of the central nervous system parenchyma. Nature 468, 253262.

K. Saijo and C.K. Glass (2011) Microglial cell origin and phenotypes in health and disease. Nature Reviews Immunology 11, 775787.

A.M. Santos , R. Calvente , M. Tassi , M.-C. Carrasco , D. Martín-Oliva , J.L. Marín-Teva (2008) Embryonic and postnatal development of microglial cells in the mouse retina. Journal of Comparative Neurology 506, 224239.

A. Sierra , J.M. Encinas , J.J.P. Deudero , J.H. Chancey , G. Enikolopov , L.S. Overstreet-Wadiche (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483495.

S.E. Smith , J. Li , K. Garbett , K. Mirnics and P.H. Patterson (2007) Maternal immune activation alters fetal brain development through interleukin-6. Journal of Neuroscience 27, 1069510702.

B. Stevens , N.J. Allen , L.E. Vazquez , G.R. Howell , K.S. Christopherson , N. Nouri (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131, 11641178.

A. Thomas , P. Gasque , D. Vaudry , B. Gonzalez and M. Fontaine (2000) Expression of a complete and functional complement system by human neuronal cells in vitro. International Immunology 12, 10151023.

M.-È. Tremblay , R.L. Lowery and A.K. Majewska (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biology 8, e1000527.

C. Verney , A. Monier , C. Fallet-Bianco and P. Gressens (2010) Early microglial colonization of the human forebrain and possible involvement in periventricular white-matter injury of preterm infants. Journal of Anatomy 217, 436448.

S. Vuillermot , E. Joodmardi , T. Perlmann , S. Ove Ögren , J. Feldon and U. Meyer (2012) Prenatal immune activation interacts with genetic nurr1 deficiency in the development of attentional impairments. Journal of Neuroscience 32, 436451.

H. Wake , A.J. Moorhouse , S. Jinno , S. Kohsaka and J. Nabekura (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. Journal of Neuroscience 29, 39743980.

S. Wakselman , C. Béchade , A. Roumier , D. Bernard , A. Triller and A. Bessis (2008) Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. Journal of Neuroscience 28, 81388143.

D.G. Walker , S.U. Kim and P.L. McGeer (1995) Complement and cytokine gene expression in cultured microglial derived from postmortem human brains. Journal of Neuroscience Research 40, 478493.

A. Cruz-Martin , M. Crespo and C. Portera-Cailliau (2010) Delayed stabilization of dendritic spines in fragile X mice. Journal of Neuroscience 30, 77937803.

S. Jung , J. Aliberti , P. Graemmel , M.J. Sunshine , G.W. Kreutzberg , A. Sher (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green flourescent protein reporter gene insertion. Molecular Cellular Biology 20, 41064114.

M. Mody , Y. Cao , Z. Cui , K.-Y. Tay , A. Shyong , E. Shimizu (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.

D.P. Schafer and B. Stevens (2010) Synapse elimination during development and disease: immune molecules take centre stage. Biochemical Society Transactions 38, 476481.

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