Neuronal synapse formation induced by microglia and interleukin 10
Open accessAbstract
Recently, it was found that microglia regulated synaptic remodeling of the developing brain, but their mechanisms have not been well understood. In this study, the action of microglia on neuronal synapse formation was investigated, and the primary target of microglial processes was discovered. When the developing microglia were applied to cultured hippocampal neurons without direct contact, the numbers of dendritic spines and excitatory and inhibitory synapses significantly increased. In order to find out the main factor for synaptic formation, the effects of cytokines released from microglia were examined. When recombinant proteins of cytokines were applied to neuronal culture media, interleukin 10 increased the numbers of dendritic spines in addition to excitatory and inhibitory synapses. Interestingly, without external stimuli, the amount of interleukin 10 released from the intact microglia appeared to be sufficient for the induction of synaptic formation. The neutralizing antibodies of interleukin 10 receptors attenuated the induction of the synaptic formation by microglia. The expression of interleukin 10 receptor was newly found in the hippocampal neurons of early developmental stage. When interleukin 10 receptors on the hippocampal neurons were knocked down with specific shRNA, the induction of synaptic formation by microglia and interleukin 10 disappeared. Pretreatment with lipopolysaccharide inhibited microglia from inducing synaptic formation, and interleukin 1β antagonized the induction of synaptic formation by interleukin 10. In conclusion, the developing microglia regulated synaptic functions and neuronal development through the interactions of the interleukin 10 released from the microglia with interleukin 10 receptors expressed on the hippocampal neurons.
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Addition of microglia to hippocampal cultures increases the number of both excitatory and inhibitory synapses through their release of IL-10.
“Addition of microglia to hippocampal cultures increases the number of both excitatory and inhibitory synapses through their release of IL-10 (Lim et al., 2013).”
From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Lim et al., 2013
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Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · see citing works
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., et al. (2011) · Science · doi:10.1126/science.1202529 · Cited by 4,244 · see citing works
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · see citing works
Microglia: Active sensor and versatile effector cells in the normal and pathologic brain
Hanisch, U.-K., & Kettenmann, H. (2007) · Nature Neuroscience · doi:10.1038/nn1997 · Cited by 3,676 · see citing works
The Classical Complement Cascade Mediates CNS Synapse Elimination
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.036 · Cited by 3,313 · see citing works
Synaptic scaling mediated by glial TNF-α
Stellwagen, D., & Malenka, R. C. (2006) · Nature · doi:10.1038/nature04671 · Cited by 1,715 · see citing works
Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis
Christopherson, K. S., Ullian, E. M., Stokes, C. C. A., Mullowney, C. E., Hell, J. W., Agah, A., Lawler, J., Mosher, D. F., Bornstein, P., & Barres, B. A. (2005) · Cell · doi:10.1016/j.cell.2004.12.020 · Cited by 1,688 · see citing works
Repertoire of microglial and macrophage responses after spinal cord injury
David, S., & Kroner, A. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3053 · Cited by 1,437 · see citing works
The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease
Barres, B. A. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.013 · Cited by 1,352 · see citing works
Control of Synaptic Strength by Glial TNFα
Beattie, E. C., Stellwagen, D., Morishita, W., Bresnahan, J. C., Ha, B. K., Von Zastrow, M., Beattie, M. S., & Malenka, R. C. (2002) · Science · doi:10.1126/science.1067859 · Cited by 1,344 · see citing works
I nterleukin -10 and R elated C ytokines and R eceptors
Pestka, S., Krause, C. D., Sarkar, D., Walter, M. R., Shi, Y., & Fisher, P. B. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104622 · Cited by 1,097 · see citing works
Microglial Activation and its Implications in the Brain Diseases
Dheen, S. T., Kaur, C., & Ling, E. (2007) · Current Medicinal Chemistry · doi:10.2174/092986707780597961 · Cited by 954 · see citing works
Functional requirement for class I MHC in CNS development and plasticity
Huh, G. S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M., & Shatz, C. J. (2000) · Science · doi:10.1126/science.290.5499.2155 · Cited by 828 · see citing works
Neuronal ‘On’ and ‘Off’ signals control microglia
Biber, K., Neumann, H., Inoue, K., & Boddeke, H. W. G. M. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.08.007 · Cited by 787 · see citing works
Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission
Pascual, O., Ben Achour, S., Rostaing, P., Triller, A., & Bessis, A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1111098109 · Cited by 693 · see citing works
Essential role of brain-derived neurotrophic factor in adult hippocampal function
Monteggia, L. M., Barrot, M., Powell, C. M., Berton, O., Galanis, V., Gemelli, T., Meuth, S., Nagy, A., Greene, R. W., & Nestler, E. J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402141101 · Cited by 685 · see citing works
Dynamics of microglial activation: A confocal time-lapse analysis in hippocampal slices
Stence, N., Waite, M., & Dailey, M. E. (2001) · Glia · doi:10.1002/1098-1136(200103)33:3 · Cited by 617 · see citing works
Regulation of Class I MHC Gene Expression in the Developing and Mature CNS by Neural Activity
Corriveau, R. A., Huh, G. S., & Shatz, C. J. (1998) · Neuron · doi:10.1016/s0896-6273(00)80562-0 · Cited by 548 · see citing works
Hoshiko, M., Arnoux, I., Avignone, E., Yamamoto, N., & Audinat, E. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1167-12.2012 · Cited by 384 · cited 2× · see citing works
“functions, including synaptic remodeling, during the development of central nervous systems [12,13,14].”
BackgroundTNFα Controls Glutamatergic Gliotransmission in the Hippocampal Dentate Gyrus
Santello, M., Bezzi, P., & Volterra, A. (2011) · Neuron · doi:10.1016/j.neuron.2011.02.003 · Cited by 362 · see citing works
Regulation of CNS synapses by neuronal MHC class I
Goddard, C. A., Butts, D. A., & Shatz, C. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702023104 · Cited by 322 · see citing works
Microglia Actively Regulate the Number of Functional Synapses
Ji, K., Akgul, G., Wollmuth, L. P., & Tsirka, S. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056293 · Cited by 280 · see citing works
Tancredi, V., D’Antuono, M., Café, C., Giovedı̀, S., Buè, M. C., D’Arcangelo, G., Onofri, F., & Benfenati, F. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0750634.x · Cited by 249 · see citing works
Bachis, A., Colangelo, A. M., Vicini, S., Doe, P. P., Bernardi, M. A. D., Brooker, G., & Mocchetti, I. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-09-03104.2001 · Cited by 196 · see citing works
Ledeboer, A., Brevé, J. J. P., Wierinckx, A., Jagt, S. V. D., Bristow, A. F., Leysen, J. E., Tilders, F. J. H., & van Dam, A. (2002) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2002.02200.x · Cited by 190 · see citing works
Attenuation of Astroglial Reactivity by Interleukin-10
Balasingam, V., & Yong, V. W. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-09-02945.1996 · Cited by 186 · see citing works
IL-10 promotes neuronal survival following spinal cord injury
Zhou, Z., Peng, X., Insolera, R., Fink, D. J., & Mata, M. M. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.08.018 · Cited by 180 · see citing works
Huang, Y., Smith, D. E., Ibáñez-Sandoval, O., Sims, J. E., & Friedman, W. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4067-11.2011 · Cited by 164 · see citing works
IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways
Sharma, S. K., Yang, B., Xi, X., et al. (2010) · Brain Research · doi:10.1016/j.brainres.2010.11.096 · Cited by 159 · see citing works
Interleukin‐10 provides direct trophic support to neurons
Zhou, Z., Peng, X., Insolera, R., Fink, D. J., & Mata, M. M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06263.x · Cited by 156 · see citing works
Zusso, M., Methot, L., Lo, R., Greenhalgh, A. D., David, S., & Stifani, S. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6182-11.2012 · Cited by 154 · see citing works
Kelly, A. M., Lynch, A. M., Vereker, E., Nolan, Y. M., Queenan, P., Whittaker, E., O'Neill, L. A. J., & Lynch, M. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m108757200 · Cited by 140 · see citing works
Kempermann, G., & Neumann, H. (2003) · Science · doi:10.1126/science.1092864 · Cited by 139 · see citing works
In vivo over‐expression of interleukin‐10 increases resistance to focal brain ischemia in mice
de Bilbao, F., Arsenijevic, D., Moll, T., Garcia, I., Vallet, P. G., Langhans, W., & Giannakopoulos, P. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06098.x · Cited by 139 · see citing works
Menachem-Zidon, O. B., Avital, A., Menahem, Y. B., Goshen, I., Kreisel, T., Shmueli, E., Segal, M., Hur, T. B., & Yirmiya, R. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.11.007 · Cited by 127 · see citing works
Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide
Richwine, A. F., Sparkman, N. L., Dilger, R. N., Buchanan, J. B., & Johnson, R. W. (2009) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2009.02.020 · Cited by 111 · see citing works
Ji, K., Yang, M., Jeong, H., Min, K., Kang, S., Jou, I., & Joe, E.-H. (2007) · Glia · doi:10.1002/glia.20571 · Cited by 107 · see citing works
Park, K. W., Lee, H. G., Jin, B. K., & Lee, Y. B. (2007) · Experimental & Molecular Medicine · doi:10.1038/emm.2007.88 · Cited by 94 · see citing works
Lim, S.-H., Kwon, S., Lee, M. K., Moon, J., Jeong, D. G., Park, E., Kim, S. J., Park, B. C., Lee, S. C., Ryu, S.-E., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.289 · Cited by 86 · see citing works
Self-citationBoyd, Z. S., Kriatchko, A., Yang, J., Agarwal, N. A., Wax, M. B., & Patil, R. V. (2003) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.03-0534 · Cited by 85 · see citing works
Resting Microglial Motility Is Independent of Synaptic Plasticity in Mammalian Brain
Wu, L., & Zhuo, M. (2008) · Journal of Neurophysiology · doi:10.1152/jn.01210.2007 · Cited by 81 · see citing works
Glial cells in synaptic plasticity
Todd, K. J., Serrano, A., Lacaille, J., & Robitaille, R. (2006) · Journal of Physiology-Paris · doi:10.1016/j.jphysparis.2005.12.002 · Cited by 74 · see citing works
Gao, X., Smith, G. M., & Chen, J. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.10.009 · Cited by 74 · see citing works
Diem, R., Hobom, M., Grötsch, P., Kramer, B., & Bähr, M. (2003) · Molecular and Cellular Neuroscience · doi:10.1016/s1044-7431(02)00042-8 · Cited by 74 · see citing works
Ji, K., Eu, M. Y., Kang, S., Gwag, B. J., Jou, I., & Joe, E.-H. (2008) · Glia · doi:10.1002/glia.20677 · Cited by 69 · see citing works
Silva, S. L., Vaz, A. R., Diógenes, M. J., et al. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.02.002 · Cited by 68 · see citing works
Park, A.-R., Oh, D., Lim, S., Choi, J., Moon, J., Yu, D.-Y., Park, S. G., Heisterkamp, N., Kim, E., Myung, P.-K., et al. (2012) · Journal of Cell Science · doi:10.1242/jcs.105502 · Cited by 36 · see citing works
Self-citationHocke, A. C., Ermert, M., Althoff, A., Brell, B., N’Guessan, P. D., Suttorp, N., & Ermert, L. (2006) · Cytokine · doi:10.1016/j.cyto.2006.01.007 · Cited by 28 · see citing works
Kaur, C., Ling, E. A., & Wong, W. C. (1987) · PubMed · Cited by 7 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [17]Kaltschmidt B, Widera D, Kaltschmidt C (2005) Signaling via NF-κB in the nervous system. Biochim Biophysic. Acta 1745: 287- 299. 15993497
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Miyamoto, A., Wake, H., Ishikawa, A. W., Eto, K., Shibata, K., Murakoshi, H., Koizumi, S., Moorhouse, A. J., Yoshimura, Y., & Nabekura, J. (2016) · Nature Communications · doi:10.1038/ncomms12540 · Cited by 649 · see citing works
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- Authors
- Lim, S.-H., Park, E., You, B., Jung, Y., Park, A.-R., Park, S. G., & Lee, J.-R.
- Affiliations
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Corresponding author
- Lee, Jae-Ran
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-11-22
- Volume
- 8
- Issue
- 11
- Pages
- e81218
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3838367
- OpenAlex
- W2035557202
- Cited by
- 224
- References
- 49
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 19 · 2023: 18 · 2022: 19 · 2021: 33 · 2020: 19 · 2019: 23 · 2018: 17 · 2017: 17 · 2016: 14 · 2015: 9 · 2014: 12
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Research Foundation
- Korea Research Institute of Bioscience and Biotechnology
- National Research Foundation of Korea (2012R1A2A2A02014520)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, synaptogenesis, IL-10, interleukin-10 receptor, dendritic spines, excitatory and inhibitory synapses, hippocampal neurons, neuronal development, lipopolysaccharide, IL-1β, synaptic remodeling
- MeSH terms
- Animals, Animals, Newborn, Hippocampus, Neuroeffector Junction, Gene Expression, Interleukin-10, Microglia, Pyramidal Cells, Rats, Interleukin-1beta, Receptors, Interleukin-10, Gene Knockdown Techniques
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