Hostname: page-component-77c89778f8-cnmwb Total loading time: 0 Render date: 2024-07-20T15:26:24.795Z Has data issue: false hasContentIssue false

The role of microglia at synapses in the healthy CNS: novel insights from recent imaging studies

Published online by Cambridge University Press:  15 March 2012

Marie-Ève Tremblay*
Department of Psychiatry, University of Wisconsin-Madison, Madison, WI 53719, USA
Correspondence should be addressed to: Marie-Ève Tremblay, Department of Psychiatry, University of Wisconsin-Madison, 6001 Research Park Boulevard, Madison, WI 53719, USA phone: 585-474-8300 email:


In the healthy brain, quiescent microglia continuously remodel their shape by extending and retracting highly motile processes. Despite a seemingly random sampling of their environment, microglial processes specifically interact with subsets of synaptic structures, as shown by recent imaging studies leading to proposed reciprocal interactions between microglia and synapses under non-pathological conditions. These studies revealed that various modalities of microglial dynamic behavior including their interactions with synaptic elements are regulated by manipulations of neurotransmission, neuronal activity and sensory experience. Conversely, these observations implied an unexpected role for quiescent microglia in the elimination of synaptic structures by specialized mechanisms that include the phagocytosis of axon terminals and dendritic spines. In light of these recent discoveries, microglia are now emerging as important effectors of neuronal circuit reorganization.

Research Article
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.)



Alvarez, A.V. and Sabatini, B.L. (2007) Anatomical and physiological plasticity of dendritic spines. Annual Review of Neuroscience 30, 7997.CrossRefGoogle ScholarPubMed
Bergles, D.E., Jabs, R. and Steinhäuser, C. (2010) Neuron–glia synapses in the brain. Brain Research Reviews 63, 130137.CrossRefGoogle ScholarPubMed
Bessis, A., Bechade, C., Bernard, D. and Roumier, A. (2007) Microglial control of neuronal death and synaptic properties. Glia 55, 233238.CrossRefGoogle ScholarPubMed
Biber, K., Neumann, H., Inoue, K. and Boddeke, H.W.G.M. (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends in Neurosciences 30, 596602.CrossRefGoogle ScholarPubMed
Bilbo, S.D., Smith, S.H. and Schwarz, J.M. (2012) A lifespan approach to neuroinflammatory and cognitive disorders: a critical role for glia. Journal of Neuroimmune Pharmacology 7, 2441.CrossRefGoogle ScholarPubMed
Blinzinger, K. and Kreutzberg, G. (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Zeitschrift für Zellforschung und mikroskopische Anatomie 85, 145157.CrossRefGoogle ScholarPubMed
Bonfanti, L. (2006) PSA-NCAM in mammalian structural plasticity and neurogenesis. Progress in Neurobiology 80, 129164.CrossRefGoogle ScholarPubMed
Cardona, A.E., Pioro, E.P., Sasse, M.E., Kostenko, V., Cardona, S.M., Dijkstra, I.M. et al. (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nature Neuroscience 9, 917924.CrossRefGoogle ScholarPubMed
Castellano, B., Gonzales, B. and Palacios, G. (1989) Cytochemical demonstration of TPPase in myelinated fibers in the central and peripheral nervous system of the rat. Brain Research 492, 203210.CrossRefGoogle ScholarPubMed
Chen, T., Koga, K., Li, X.-Y. and Zhuo, M. (2010) Spinal microglial motility is independent of neuronal activity and plasticity in adult mice. Molecular Pain 6, 19.CrossRefGoogle ScholarPubMed
Cho, S.H., Sun, B., Zhou, Y., Kauppinen, T.M., Halabisky, B., Wes, P. et al. (2011) CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. Journal of Biological Chemistry 286, 3271332722.CrossRefGoogle Scholar
Choi, M.S., Cho, K.S., Shin, S.M., Ko, H.M., Kwon, K.J., Shin, C.Y. et al. (2010) ATP induced microglial cell migration through non-transcriptional activation of matrix metalloproteinase-9. Archives of Pharmacal Research 33, 257265.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
De Paola, V., Holtmaat, A., Knott, G., Song, S., Wilbrecht, L., Caroni, P. et al. (2006) Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex. Neuron 49, 861875.CrossRefGoogle ScholarPubMed
Del Rio-Hortega, P. (1919) El tercer elemento de los centros nerviosos I La microglia en estado normal II Intervencíon de la microglia en los procesos patológicos III Naturaleza probable de la microglia. Boletín de la Sociedad Española de Biología 9, 69120.Google Scholar
Del Rio-Hortega, P. (1932) Microglia. In Penfield, W. (ed.) Cytology and Cellular Pathology of the Nervous System, New York: Hoeber. pp. 482534.Google Scholar
Dibaj, P., Nadrigny, F., Steffens, H., Scheller, A., Hirrlinger, J., Schomburg, E.D. et al. (2010) NO mediates microglial response to acute spinal cord injury under ATP control in vivo. Glia 58, 11331144.CrossRefGoogle ScholarPubMed
Donnelly, D.J., Longbrake, E.E., Shawler, T.M., Kigerl, K.A., Lai, W., Tovar, C.A. et al. (2011) Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. Journal of Neuroscience 31, 99109922.CrossRefGoogle ScholarPubMed
Eom, T.-Y., Stanco, A., Weimer, J., Stabingas, K., Sibrack, E., Gukassyan, V. et al. (2011) Direct visualization of microtubules using a genetic tool to analyse radial progenitor-astrocyte continuum in brain. Nature Communications 2, 446.CrossRefGoogle ScholarPubMed
Feng, G., Mellor, R.H., Bernstein, M., Keller-Peck, C., Nguyen, Q.T., Wallace, M. et al. (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 4151.CrossRefGoogle ScholarPubMed
Fields, R.D. and Burnstock, G. (2006) Purinergic signalling in neuron–glia interactions. Nature Reviews. Neuroscience 7, 423436.CrossRefGoogle ScholarPubMed
Fontainhas, A.M., Wang, M.H., Liang, K.J., Chen, S., Mettu, P., Damani, M. et al. (2011) Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. Plos One 6,14.CrossRefGoogle ScholarPubMed
Fortin, D.A., Srivastava, T. and Soderling, T.R. (2011) Structural modulation of dendritic spines during synaptic plasticity. The Neuroscientist.Google ScholarPubMed
Fuhrmann, M., Bittner, T., Jung, C.K., Burgold, S., Page, R.M., Mitteregger, G. et al. (2010) Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nature Neuroscience 13, 411413.CrossRefGoogle Scholar
Graeber, M.B. (2010) Changing face of microglia. Science 330, 783788.CrossRefGoogle ScholarPubMed
Halassa, M.M. and Haydon, P.G. (2010) Astrocytic networks modulate neuronal activity and behavior. Annual Review of Physiology 72, 335355.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
Harrison, J.K., Jiang, Y., Chen, S., Xia, Y., Maciejewski, D., McNamara, R.K. et al. (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proceedings of the National Academy of Sciences of the U.S.A. 95, 1089610901.CrossRefGoogle ScholarPubMed
Haynes, S.E., Hollopter, G., Yang, G., Kurpius, D., Dailey, M.E., Gan, W.-B. et al. (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nature Neuroscience 9, 15121519.CrossRefGoogle ScholarPubMed
Herndon, R.M. (1964) The fine structure of the rat cerebellum. II. The stellate neurons, granule cells, and glia. Journal of Cell Biology 23, 277293.CrossRefGoogle ScholarPubMed
Hirasawa, T., Ohsawa, K., Imai, Y., Ondo, Y., Akazawa, C., Uchino, S. et al. (2005) Visualization of microglia in living tissues using Iba1-EGFP transgenic mice. Journal of Neuroscience Research 81, 357362.CrossRefGoogle ScholarPubMed
Hirrlinger, P.G., Scheller, A., Braun, C., Quintela-Schneider, M., Fuss, B., Hirrlinger, J. et al. (2005) Expression of reef coral fluorescent proteins in the central nervous system of transgenic mice. Molecular and Cellular Neuroscience 30, 291303.CrossRefGoogle ScholarPubMed
Holtmaat, A., Wilbrecht, L., Knott, G.W., Welker, E. and Svoboda, K. (2006) Experience-dependent and cell-type-specific spine growth in the neocortex. Nature 441, 979983.CrossRefGoogle ScholarPubMed
Holtmaat, A. and Svoboda, K. (2009) Experience-dependent structural synaptic plasticity in the mammalian brain. Nature Reviews. Neuroscience 10, 647658.CrossRefGoogle ScholarPubMed
Honda, S., Sasaki, Y., Ohsawa, K., Imai, Y., Nakamura, Y., Inoue, K. et al. (2001) Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. Journal of Neuroscience 21, 19751982.CrossRefGoogle ScholarPubMed
Hooks, B.M. and Chen, C. (2007) Critical periods in the visual system: changing views for a model of experience-dependent plasticity. Neuron 56, 312326.CrossRefGoogle Scholar
Hughes, E.G., Fukaya, M., Kang, S.H. and Bergles, D.E. (2011)In vivo dynamics of NG2+ glial cells in the adult brain. Abstract Viewer/Itinerary Planner. Society for Neuroscience, Program No. 548.12.Google Scholar
Inoue, K., Koizumi, S. and Tsuda, M. (2007) The role of nucleotides in the neuron–glia communication responsible for the brain functions. Journal of Neurochemistry 102, 14471458.CrossRefGoogle ScholarPubMed
Ito, D., Imai, Y., Ohsawa, K., Nakajima, K., Fukuuchi, Y. and Kohsaka, S. (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Molecular Brain Research 57, 19.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 fluorescent protein reporter gene insertion. Molecular and Cellular Biology 20, 41064114.CrossRefGoogle ScholarPubMed
Kang, J., Kang, N., Lovatt, D., Torres, A., Zhao, Z., Lin, J. et al. (2008) Connexin 43 hemichannels are permeable to ATP. Journal of Neuroscience 28, 47024711.CrossRefGoogle ScholarPubMed
Keck, T., Mrsic-Flogel, T.D., Vaz Afonso, M., Eysel, U.T., Bonhoeffer, T. and Hübener, M. (2008) Massive restructuring of neuronal circuits during functional reorganization of adult visual cortex. Nature Neuroscience 11, 11621167.CrossRefGoogle ScholarPubMed
Kettenmann, H., Hanisch, U.K., Noda, M. and Verkhratsky, A. (2011) Physiology of microglia. Physiological Reviews 91, 461553.CrossRefGoogle ScholarPubMed
Knott, G.W., Holtmaat, A., Wilbrecht, L., Welker, E. and Svoboda, K. (2006) Spine growth precedes synapse formation in the adult neocortex in vivo. Nature Neuroscience 9, 11171124.CrossRefGoogle ScholarPubMed
Kreutzberg, G.W. (1996) Microglia: a sensor for pathological events in the CNS. Trends in Neurosciences 19, 312318.CrossRefGoogle ScholarPubMed
Kumamoto, T., Nakagawa, S., Yata, Y. and Shimizu, E. (1976) On the histochemistry of enuronal and glial TPPase. Histochemistry 47, 101109.CrossRefGoogle Scholar
Le Roy, C. and Wrana, J.L. (2005) Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nature Reviews. Molecular Cell Biology 6, 112126.CrossRefGoogle ScholarPubMed
Liang, K.J., Lee, J.E., Wang, Y.D., Ma, W., Fontainhas, A.M., Fariss, R.N. et al. (2009) Regulation of dynamic behavior of retinal microglia by CX3CR1 signaling. Investigative Ophthalmology & Visual Science 50, 44444451.CrossRefGoogle ScholarPubMed
Liu, D., Wang, Z., Liu, S., Wang, F., Zhao, S. and Hao, A. (2011) Anti-inflammatory effects of fluoxetine in lipopolysaccharide(LPS)-stimulated microglial cells. Neuropharmacology 61, 592599.CrossRefGoogle ScholarPubMed
Liu, G.J., Nagarajah, R., Banati, R.B. and Bennett, M.R. (2009) Glutamate induces directed chemotaxis of microglia. European Journal of Neuroscience 29, 11081118.CrossRefGoogle ScholarPubMed
MacVicar, B.A. and Thompson, R.J. (2010) Non-junction functions of pannexin-1 channels. Trends in Neurosciences 33, 93102.CrossRefGoogle ScholarPubMed
Majewska, A. and Sur, M. (2003) Motility of dendritic spines in visual cortex in vivo: changes during the critical period and effects of visual deprivation. Proceedings of the National Academy of Sciences of the U.S.A. 100, 1602416029.CrossRefGoogle ScholarPubMed
Majewska, A.K., Newton, J.R. and Sur, M. (2006) Remodeling of synaptic structure in sensory cortical areas in vivo. Journal of Neuroscience 26, 30213029.CrossRefGoogle ScholarPubMed
Marker, D.F., Tremblay, M.E., Lu, S.M., Majewska, A.K. and Gelbard, H.A. (2010) A thin- skull window technique for chronic two-photon in vivo imaging of murine microglia in models of neuroinflammation. Journal of Visualized Experiments 43, e2059.Google Scholar
Mataga, N., Mizuguchi, Y. and Hensch, T.K. (2004) Experience-dependent pruning of dendritic spines in visual cortex by tissue plasminogen activator. Neuron 44, 10311041.CrossRefGoogle ScholarPubMed
Mori, S. and Leblond, C.P. (1969) Indentification of microglia in light and electron microscopy. Journal of Comparative Neurology 135, 5780.CrossRefGoogle Scholar
Murabe, Y. and Sano, Y. (1982) Morphological studies on neuroglia. V. Microglial cells in the cerebral cortex of the rat, with special reference to their possible involvement in synaptic function. Cell and Tissue Research 223, 493506.Google ScholarPubMed
Nakanishi, H. (2003) Microglial functions and proteases. Molecular Neurobiology 27, 163176.CrossRefGoogle ScholarPubMed
Napoli, I. and Neumann, H. (2009) Microglial clearance function in health and disease. Neuroscience 158, 10301038.CrossRefGoogle ScholarPubMed
Neumann, H., Kotter, M.R. and Franklin, R.J.M. (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132, 288295.CrossRefGoogle Scholar
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
Oray, S., Majewska, A. and Sur, M. (2004) Dendritic spine dynamics are regulated by monocular deprivation and extracellular matrix degradation. Neuron 33, 10211030.CrossRefGoogle Scholar
Orr, A.G., Orr, A.L., Li, X.-J., Gross, R.E. and Traynelis, S.F. (2009) Adenosine A2A receptor mediates microglial process retraction. Nature Neuroscience 12, 872880.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 333, 14561458.CrossRefGoogle ScholarPubMed
Perry, V.H. and O'Connor, V. (2010) The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective. ASN Neuro 2, e00047.CrossRefGoogle ScholarPubMed
Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J.W. and Maffei, L. (2002) Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 12481251.CrossRefGoogle ScholarPubMed
Pocock, J.M. and Kettenmann, H. (2007) Neurotransmitter receptors on microglia. Trends in Neurosciences 30, 527535.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
Prinz, M., Priller, J., Sisodia, S.S. and Ransohoff, R.M. (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nature Neuroscience 14, 12271235.CrossRefGoogle ScholarPubMed
Ransohoff, R.M. and Perry, V.H. (2009) Microglial physiology: unique stimuli, secialized responses. Annual Review of Immunology 27, 119145.CrossRefGoogle Scholar
Rivest, S. (2009) Regulation of innate immune responses in the brain. Nature Reviews. Immunology 9, 429439.CrossRefGoogle ScholarPubMed
Schafer, D.P., Lehrman, E.K., Kautzman, A.G., Koyama, R., Mardinly, A.R., Greenberg, M.E. et al. (2011)Microglia shape neural circuits in the developing brain. Abstract Viewer/Itinerary Planner. Society for Neuroscience, Program No. 663.03.Google Scholar
Schmechel, D.E. (1999) Assessment of ultrastructural changes associated with apoptosis. In Hannun, Y.A. and Boustany, R.-M. (eds.) Apoptosis in Neurobiology, Boca Raton: CRC Press. pp. 161163.Google Scholar
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
Silverman, W., Locovei, S. and Dahl, G. (2008) Probenecid, a gout remedy, inhibits pannexin 1 channels. American Journal of Physiology. Cell Physiology 295, C761C767.CrossRefGoogle Scholar
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
Syková, E. and Nicholson, C. (2008) Diffusion in brain extracellular space. Physiological Reviews 88, 12771340.CrossRefGoogle ScholarPubMed
Theodosis, D.T., Poulain, D.A. and Oliet, S.H.R. (2008) Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiological Reviews 88, 9831008.CrossRefGoogle ScholarPubMed
Trachtenberg, J.T., Chen, B.E., Knott, G.W., Feng, G., Sanes, J.R., Welker, E. et al. (2002) Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788794.CrossRefGoogle ScholarPubMed
Trapp, B.D., Wujek, J.R., Criste, G.A., Jalabi, W., Yin, X., Kidd, G.J. et al. (2007) Evidence for synaptic stripping by cortical microglia. Glia 55, 360368.CrossRefGoogle ScholarPubMed
Tremblay, M.E., Riad, M. and Majewska, A. (2010a) Preparation of mouse brain tissue for immunoelectron microscopy. Journal of Visualized Experiments 41, e2021.Google Scholar
Tremblay, M.E., Lowery, R.L. and Majewska, A.K. (2010b) Microglial interactions with synapses are modulated by visual experience. PloS Biology 8, e1000527.CrossRefGoogle ScholarPubMed
Tremblay, M.E., Stevens, B., Sierra, A., Wake, H., Bessis, A. and Nimmerjahn, A. (2011) The role of microglia in the healthy brain. Journal of Neuroscience 31, 1606416069.CrossRefGoogle ScholarPubMed
Tremblay, M.E., Zettel, M.L., Ison, J.R., Allen, P.D. and Majewska, A.K. (2012) Effects of aging and sensory loss on glial cells in visual and auditory cortices. Glia 60, 541558.CrossRefGoogle ScholarPubMed
Ventura, R. and Harris, K.M. (1999) Three-dimensional relationships between hipocampal synapses and astrocytes. Journal of Neuroscience 19, 68976906.CrossRefGoogle Scholar
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
Wang, Y. and Neumann, H. (2010) Alleviation of neurotoxicity by microglial human Siglec-11. Journal of Neuroscience 30, 34823488.CrossRefGoogle ScholarPubMed
Willig, K.I., Kellner, R.R., Medda, R., Hein, B., Jakobs, S. and Hell, S.W. (2006) Nanoscale resolution in GFP-based microscopy. Nature Methods 3, 721723.CrossRefGoogle ScholarPubMed
Wong, W.T., Wang, M. and Li, W. (2011) Regulation of microglia by ionotropic glutamatergic and GABAergic neurotransmission. Neuron Glia Biology 14, 16.Google Scholar
Wu, L.-J. and Zhuo, M. (2008) Resting microglial motility is independent of synaptic plasticity in mammalian brain. Journal of Neurophysiology 99, 20262032.CrossRefGoogle ScholarPubMed
Yang, P., Yin, X. and Rutishauser, U. (1992) Intercellular space is affected by the polysialic acid content of NCAM. Journal of Cell Biology 116, 14871496.CrossRefGoogle ScholarPubMed
Yang, G., Pan, F., Parkhurst, C.N., Grutzendler, J. and Gan, W.B. (2010) Thinned-skull cranial window technique for long-term imaging of the cortex in living mice. Nature Protocols 5, 201208.CrossRefGoogle Scholar
Zuo, Y., Lin, A., Chang, P. and Gan, W.B. (2005) Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181189.CrossRefGoogle ScholarPubMed