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PLOS ONE  2013 

Neuronal Synapse Formation Induced by Microglia and Interleukin 10

DOI: 10.1371/journal.pone.0081218

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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.


[1]  Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60: 430-440. doi:10.1016/j.neuron.2008.10.013. PubMed: 18995817.
[2]  Kempermann G, Neumann H (2003) Micorglia: the enemy within? Science 302: 1689-1690. doi:10.1126/science.1092864. PubMed: 14657479.
[3]  David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12: 388-399. doi:10.1038/nrn3053. PubMed: 21673720.
[4]  Dheen ST, Kaur C, Ling EA (2007) Microglial activation and its implications in the brain diseases. Curr Med Chem 14: 1189-1197. doi:10.2174/092986707780597961. PubMed: 17504139.
[5]  Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10: 1387-1394. doi:10.1038/nn1997. PubMed: 17965659.
[6]  Ji KA, Yang MS, Jeong HK, Min KJ, Kang SH, Jou I, Joe EH (2007) Resident microglia die and infiltrated neutrophils and monocytes become major inflammatory cells in lipopolysaccharide-injected brain. Glia 55: 1577-1588. doi:10.1002/glia.20571. PubMed: 17823975.
[7]  Ji KA, Eu MY, Kang SH, Gwag BJ, Jou I, Joe EH (2008) Differential neutrophil infiltration contributes to regional differences in brain inflammation in the substantia nigra pars compacta and cortex. Glia 56: 1039-1047. doi:10.1002/glia.20677. PubMed: 18381656.
[8]  Biber K, Neumann H, Inoue K, Boddeke HWGM (2007) Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci 30: 596-602. doi:10.1016/j.tins.2007.08.007. PubMed: 17950926.
[9]  Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314-1318. doi:10.1126/science.1110647. PubMed: 15831717.
[10]  Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: A confocal time-lapse analysis in hippocampal slices. Glia 33: 256-266. doi:10.1002/1098-1136(200103)33:3. PubMed: 11241743.
[11]  Wu LJ, Zhuo M (2008) Resting microglial motility is independent of synaptic plasticity in mammalian brain. J Neurophysiol 99: 2026-2032. doi:10.1152/jn.01210.2007. PubMed: 18256162.
[12]  Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M et al. (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333: 1456-1458. doi:10.1126/science.1202529. PubMed: 21778362.
[13]  Hoshiko M, Arnoux I, Avignone E, Yamamoto N, Audinat E (2012) Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J Neurosci 32: 15106-15111. doi:10.1523/JNEUROSCI.1167-12.2012. PubMed: 23100431.
[14]  Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR et al. (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74: 691-705. doi:10.1016/j.neuron.2012.03.026. PubMed: 22632727.
[15]  Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK et al. (2002) Control of synaptic strength by glial TNFα. Science 295: 2282-2285. doi:10.1126/science.1067859. PubMed: 11910117.
[16]  Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-α. Nature 440: 1054-1059. doi:10.1038/nature04671. PubMed: 16547515.
[17]  Kaltschmidt B, Widera D, Kaltschmidt C (2005) Signaling via NF-κB in the nervous system. Biochim Biophysic. Acta 1745: 287-299.
[18]  Santello M, Bezzi P, Volterra A (2011) TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69: 988-1001. doi:10.1016/j.neuron.2011.02.003. PubMed: 21382557.
[19]  Pascual O, Achoura SB, Rostaing P, Triller A, Bessis A (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A 109: E197-E205. doi:10.1073/pnas.1104767109. PubMed: 22167804.
[20]  Christopherson KS, Ullian EM, Stokes CCA, Mullowney CE, Hell JW et al. (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120: 421-433. doi:10.1016/j.cell.2004.12.020. PubMed: 15707899.
[21]  Kelly A, Lynch A, Vereker E, Nolan Y, Queenan P et al. (2001) The anti-inflammatory cytokine, interleukin (IL)-10, blocks the inhibitory effect of IL-1β on long term potentiation. J Biol Chem 276: 45564-45572. doi:10.1074/jbc.M108757200. PubMed: 11581275.
[22]  Menachem-Zidon OB, Avital A, Ben-Menahem Y, Goshen I, Kreisel T et al. (2011) Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling. Brain Behav Immun 25: 1008-1016. doi:10.1016/j.bbi.2010.11.007. PubMed: 21093580.
[23]  Silva SL, Vaz AR, Diógenes MJ, van Rooijen N, Sebasti?o AM et al. (2012) Neuritic growth impairment and cell death by unconjugated bilirubin is mediated by NO and glutamate, modulated by microglia, and prevented by glycoursodeoxycholic acid and interleukin-10. Neuropharmacology 62: 2398-2408. doi:10.1016/j.neuropharm.2012.02.002. PubMed: 22361233.
[24]  Balasingam V, Yong VW (1996) Attenuation of astroglial reactivity by interleukin-10. J Neurosci 16: 2945-2955. PubMed: 8622125.
[25]  Park KW, Lee HG, Jin BK, Lee YB (2007) Interleukin-10 endogenously expressed in microglia prevents lipopolysaccharide-induced neurodegeneration in the rat cerebral cortex in vivo. Exp Mol Med 39: 812-819. doi:10.1038/emm.2007.88. PubMed: 18160852.
[26]  Richwine AF, Sparkman NL, Dilger RN, Buchanan JB, Johnson RW (2009) Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 23: 794-802. doi:10.1016/j.bbi.2009.02.020. PubMed: 19272439.
[27]  Zhou Z, Peng X, Insolera R, Fink DJ, Mata M (2009) Interleukin-10 provides direct trophic support to neurons. J Neurochem 110: 1617-1627. doi:10.1111/j.1471-4159.2009.06263.x. PubMed: 19575707.
[28]  Sharma S, Yang B, Xi XP, Grotta JC, Aronowski J et al. (2011) IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res 1373: 189-194. doi:10.1016/j.brainres.2010.11.096. PubMed: 21138740.
[29]  Zusso M, Methot L, Lo R, Greenhalgh AD, David S et al. (2012) Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor Runx1. J Neurosci 32: 11285-11298. doi:10.1523/JNEUROSCI.6182-11.2012. PubMed: 22895712.
[30]  Kaur C, Ling EA, Wong WC (1987) Localisation of thiamine pyrophosphatase in the amboeboid microglial cells in the brain of postnatal rats. J Anat 152: 13-22. PubMed: 2820912.
[31]  Diem R, Hobom M, Gr?tsch P, Kramer B, B?hr M (2003) Interleukin-1β protects neurons via the interleukin-1 (IL-1) receptor-mediated Akt pathway and by IL-1 receptor-independent decrease of transmembrane currents in vivo. Mol Cell Neurosci 22: 487-500. doi:10.1016/S1044-7431(02)00042-8. PubMed: 12727445.
[32]  Ledeboer A, Brevé JJP, Wierinckx A, van der Jagt S, Bristow AF et al. (2002) Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. Eur J Neurosci 16: 1175-1185. doi:10.1046/j.1460-9568.2002.02200.x. PubMed: 12405978.
[33]  Zhou Z, Peng X, Insolera R, Fink DJ, Mata M (2009) IL-10 promotes neuronal survival following spinal cord injury. Exp Neurol 220: 183-190. doi:10.1016/j.expneurol.2009.08.018. PubMed: 19716366.
[34]  Huang Y, Smith DE, Ibá?ez-Sandoval O, Sims JE, Friedman WJ (2011) Neuron-specific effects of Interleukin-1b are mediated by a novel isoform of the IL-1 receptor accessory protein. J Neurosci 31: 18048-18059. doi:10.1523/JNEUROSCI.4067-11.2011. PubMed: 22159118.
[35]  Ji K, Akgul G, Wollmuth LP, Tsirka SE (2013) Microglia actively regulate the number of functional synapses. PLOS ONE 8: e56293-e56293. doi:10.1371/journal.pone.0056293. PubMed: 23393609.
[36]  Bachis A, Colangelo AM, Vicini S, Doe PP, De Bernardi MA et al. (2001) Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci 21: 3104-3112. PubMed: 11312295.
[37]  De Bilbao F, Arsenijevic D, Moll T, Garcia-Gabay I, Vallet P et al. (2009) In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice. J Neurochem 110: 12-22. doi:10.1111/j.1471-4159.2009.06098.x. PubMed: 19457075.
[38]  Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y et al. (2004) Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 22: 929-979. doi:10.1146/annurev.immunol.22.012703.104622. PubMed: 15032600.
[39]  Corriveau RA, Huh GS, Shatz CJ (1998) Regulation of Class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21: 505-520. doi:10.1016/S0896-6273(00)80562-0. PubMed: 9768838.
[40]  Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM et al. (2000) Functional requirement for Class I MHC in CNS development and plasticity. Science 290: 2155-2159. doi:10.1126/science.290.5499.2155. PubMed: 11118151.
[41]  Goddard CA, Butts DA, Shatz CJ (2007) Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci U S A 104: 6828-6833. doi:10.1073/pnas.0702023104. PubMed: 17420446.
[42]  Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS et al. (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131: 1164-1178. doi:10.1016/j.cell.2007.10.036. PubMed: 18083105.
[43]  Tancredi V, D’Antuono M, Cafè C, Giovedì S, Buè MC et al. (2000) The inhibitory effects of interleukin-6 on synaptic plasticity in the rat hippocampus are associated with an inhibition of mitogen-activated protein kinase ERK. J Neurochem 75: 634-643. PubMed: 10899938.
[44]  Gao X, Smith GM, Chen J (2009) Impaired dendritic development and synaptic formation of postnatal-born dentate gyrus granular neurons in the absence of brain-derived neurotrophic factor signaling. Exp Neurol 215: 178-190. doi:10.1016/j.expneurol.2008.10.009. PubMed: 19014937.
[45]  Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V et al. (2004) Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci U S A 101: 10827-10832. doi:10.1073/pnas.0402141101. PubMed: 15249684.
[46]  Todd KJ, Serrano A, Lacaille JC, Robitaille R (2005) Glial cells in synaptic plasticity. J Physiol 99: 75-83. PubMed: 16446078.
[47]  Hocke AC, Ermert M, Althoff A, Brell B, N’Guessan PD et al. (2006) Regulation of interleukin IL-4, IL-13, IL-10, and their downstream components in lipopolysaccharide-exposed rat lungs. Comparison of the constitutive expression between rats and humans. Cytokine 33: 199-211. doi:10.1016/j.cyto.2006.01.007. PubMed: 16522370.
[48]  Boyd ZS, Kriatchko A, Yang J, Agarwal N, Wax MB, et al. (2003) Interleukin-10 receptor signaling through STAT-3 regulates the apoptosis of retinal ganglion cells in response to stress. Inv Oph Vis Sic 44: 5206-5211.
[49]  Park AR, Oh D, Lim SH, Choi J, Moon J et al. (2012) Regulation of dendritic arborization by BCR Rac1 GTPase-activating protein, a new substrate of protein tyrosine phosphatase receptor T. J Cell Sci 125: 4518-4531. doi:10.1242/jcs.105502. PubMed: 22767509.
[50]  Lim SH, Kwon SK, Lee MK, Moon J, Jeong DG et al. (2009) Synapse formation regulated by protein tyrosine phosphatase receptor T through interaction with cell adhesion molecules and Fyn. EMBO J 28: 3564-3578. doi:10.1038/emboj.2009.289. PubMed: 19816407.


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