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Activation of mGluR1 Mediates C1q-Dependent Microglial Phagocytosis of Glutamatergic Synapses in Alzheimer’s Rodent Models

  • Bihua Bie
  • Jiang Wu
  • Joseph F. Foss
  • Mohamed NaguibEmail author
Article

Abstract

Microglia and complements appear to be involved in the synaptic and cognitive deficits in Alzheimer’s disease (AD), though the mechanisms remain elusive. In this study, utilizing two types of rodent model of AD, we reported increased complement C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses, which led to synaptic and cognitive deficits. We also found increased activity of the metabotropic glutamate receptor 1 (mGluR1) in hippocampal CA1 in the modeled rodents. Artificial activation of mGluR1 signaling promoted dephosphorylation of fragile X mental retardation protein (FMRP) and facilitated the local translation machinery of synaptic C1q mRNA, thus mimicking the C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses and synaptic and cognitive deficiency in the modeled rodents. However, suppression of mGluR1 signaling inhibited the dephosphorylation of FMRP and repressed the local translation of synaptic C1q mRNA, which consequently alleviated microglial phagocytosis of synapses and restored the synaptic and cognitive function in the rodent models. These findings illustrate a novel molecular mechanism underlying C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses in AD.

Keywords

Alzheimer’s disease Complement C1q Metabotropic glutamate receptor Fragile X mental retardation protein Microglial phagocytosis Synaptic loss 

Notes

Acknowledgements

The authors thank John Peterson, Ph.D., Imaging Core, Cleveland Clinic for his expertise and help provided for imaging analysis.

Funding Information

Dr. Naguib is supported by the National Institute of Aging of the National Institutes of Health under Award Number R56AG051594. This work utilized the Leica SP8 confocal microscope that was purchased with funding from the National Institutes of Health SIG grant1S10OD019972-01.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1467_MOESM4_ESM.docx (283 kb)
ESM 1 (DOCX 283 kb)

References

  1. 1.
    Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842.  https://doi.org/10.1038/nm1782 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Sun B, Halabisky B, Zhou Y, Palop JJ, Yu G, Mucke L, Gan L (2009) Imbalance between GABAergic and glutamatergic transmission impairs adult neurogenesis in an animal model of Alzheimer’s disease. Cell Stem Cell 5(6):624–633.  https://doi.org/10.1016/j.stem.2009.10.003 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bie B, Wu J, Yang H, Xu JJ, Brown DL, Naguib M (2014) Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency. Nat Neurosci 17(2):223–231.  https://doi.org/10.1038/nn.3618. http://www.nature.com/neuro/journal/vaop/ncurrent/abs/nn.3618.html#supplementary-information. Accessed 19 Jan 2014
  4. 4.
    Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8(11):e1000527.  https://doi.org/10.1371/journal.pbio.1000527 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tremblay ME, Majewska AK (2011) A role for microglia in synaptic plasticity? Commun Integr Biol 4(2):220–222.  https://doi.org/10.4161/cib.4.2.14506 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME et al (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74(4):691–705.  https://doi.org/10.1016/j.neuron.2012.03.026 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Schafer DP, Stevens B (2013) Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. Curr Opin Neurobiol 23(6):1034–1040.  https://doi.org/10.1016/j.conb.2013.09.012 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333(6048):1456–1458.  https://doi.org/10.1126/science.1202529 CrossRefPubMedGoogle Scholar
  9. 9.
    Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77(1):10–18.  https://doi.org/10.1016/j.neuron.2012.12.023 CrossRefPubMedGoogle Scholar
  10. 10.
    Wake H, Moorhouse AJ, Miyamoto A, Nabekura J (2013) Microglia: actively surveying and shaping neuronal circuit structure and function. Trends Neurosci 36(4):209–217.  https://doi.org/10.1016/j.tins.2012.11.007 CrossRefPubMedGoogle Scholar
  11. 11.
    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science.  https://doi.org/10.1126/science.aad8373
  12. 12.
    Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, Shang Y, Oldham MC et al (2016) Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165(4):921–935.  https://doi.org/10.1016/j.cell.2016.04.001 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11(9):785–797.  https://doi.org/10.1038/ni.1923 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Stephan AH, Barres BA, Stevens B (2012) The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci 35:369–389.  https://doi.org/10.1146/annurev-neuro-061010-113810 CrossRefPubMedGoogle Scholar
  15. 15.
    Bialas AR, Stevens B (2013) TGF-[beta] signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci 16(12):1773–1782.  https://doi.org/10.1038/nn.3560. http://www.nature.com/neuro/journal/v16/n12/abs/nn.3560.html#supplementary-information. Accessed 27 Oct 2013CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468(7321):253–262CrossRefGoogle Scholar
  17. 17.
    Zhang J, Malik A, Choi HB, Ko RW, Dissing-Olesen L, Macvicar BA (2014) Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 82(1):195–207.  https://doi.org/10.1016/j.neuron.2014.01.043 CrossRefPubMedGoogle Scholar
  18. 18.
    Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, Kim L, Tsai HH et al (2013) A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci 33(33):13460–13474.  https://doi.org/10.1523/JNEUROSCI.1333-13.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wang DO, Martin KC, Zukin RS (2010) Spatially restricting gene expression by local translation at synapses. Trends Neurosci 33(4):173–182.  https://doi.org/10.1016/j.tins.2010.01.005 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Poon MM, Choi SH, Jamieson CA, Geschwind DH, Martin KC (2006) Identification of process-localized mRNAs from cultured rodent hippocampal neurons. J Neurosci 26(51):13390–13399.  https://doi.org/10.1523/JNEUROSCI.3432-06.2006 CrossRefPubMedGoogle Scholar
  21. 21.
    Wang DO, Kim SM, Zhao Y, Hwang H, Miura SK, Sossin WS, Martin KC (2009) Synapse- and stimulus-specific local translation during long-term neuronal plasticity. Science 324(5934):1536–1540.  https://doi.org/10.1126/science.1173205 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wu J, Bie B, Naguib M (2016) Epigenetic manipulation of brain-derived neurotrophic factor improves memory deficiency induced by neonatal anesthesia in rats. Anesthesiology 124(3):624–640.  https://doi.org/10.1097/aln.0000000000000981 CrossRefPubMedGoogle Scholar
  23. 23.
    Ashley CT Jr, Wilkinson KD, Reines D, Warren ST (1993) FMR1 protein: conserved RNP family domains and selective RNA binding. Science 262(5133):563–566CrossRefGoogle Scholar
  24. 24.
    Bassell GJ, Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60(2):201–214.  https://doi.org/10.1016/j.neuron.2008.10.004 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hamilton A, Esseltine JL, DeVries RA, Cregan SP, Ferguson SS (2014) Metabotropic glutamate receptor 5 knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer’s disease. Mol Brain 7:40.  https://doi.org/10.1186/1756-6606-7-40
  26. 26.
    Aschrafi A, Cunningham BA, Edelman GM, Vanderklish PW (2005) The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain. Proc Natl Acad Sci U S A 102(6):2180–2185.  https://doi.org/10.1073/pnas.0409803102 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Di Prisco GV, Huang W, Buffington SA, Hsu CC, Bonnen PE, Placzek AN, Sidrauski C, Krnjevic K et al (2014) Translational control of mGluR-dependent long-term depression and object-place learning by eIF2alpha. Nat Neurosci 17(8):1073–1082.  https://doi.org/10.1038/nn.3754 CrossRefPubMedGoogle Scholar
  28. 28.
    Ostapchenko VG, Beraldo FH, Guimaraes AL, Mishra S, Guzman M, Fan J, Martins VR, Prado VF et al (2013) Increased prion protein processing and expression of metabotropic glutamate receptor 1 in a mouse model of Alzheimer’s disease. J Neurochem 127(3):415–425.  https://doi.org/10.1111/jnc.12296 CrossRefPubMedGoogle Scholar
  29. 29.
    Chen X, Lin R, Chang L, Xu S, Wei X, Zhang J, Wang C, Anwyl R et al (2013) Enhancement of long-term depression by soluble amyloid beta protein in rat hippocampus is mediated by metabotropic glutamate receptor and involves activation of p38MAPK, STEP and caspase-3. Neuroscience 253:435–443.  https://doi.org/10.1016/j.neuroscience.2013.08.054 CrossRefPubMedGoogle Scholar
  30. 30.
    Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459(7243):55–60.  https://doi.org/10.1038/nature07925 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bie B, Zhang Z, Cai YQ, Zhu W, Zhang Y, Dai J, Lowenstein CJ, Weinman EJ et al (2010) Nerve growth factor-regulated emergence of functional delta-opioid receptors. J Neurosci 30(16):5617–5628.  https://doi.org/10.1523/JNEUROSCI.5296-09.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Chacon MA, Barria MI, Soto C, Inestrosa NC (2004) Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits. Mol Psychiatry 9(10):953–961.  https://doi.org/10.1038/sj.mp.4001516 CrossRefPubMedGoogle Scholar
  33. 33.
    Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, vol 1, 4th edn. Academic, New YorkGoogle Scholar
  34. 34.
    Bie B, Wu J, Foss JF, Naguib M (2018) Amyloid fibrils induce dysfunction of hippocampal glutamatergic silent synapses. Hippocampus 28(8):549–556.  https://doi.org/10.1002/hipo.22955 CrossRefPubMedGoogle Scholar
  35. 35.
    Wu J, Bie B, Yang H, Xu JJ, Brown DL, Naguib M (2013) Activation of the CB(2) receptor system reverses amyloid-induced memory deficiency. Neurobiol Aging 34:791–804.  https://doi.org/10.1016/j.neurobiolaging.2012.06.011 CrossRefPubMedGoogle Scholar
  36. 36.
    Wu J, Bie B, Yang H, Xu JJ, Brown DL, Naguib M (2013) Suppression of central chemokine fractalkine receptor signaling alleviates amyloid-induced memory deficiency. Neurobiol Aging 34(12):2843–2852.  https://doi.org/10.1016/j.neurobiolaging.2013.06.003 CrossRefPubMedGoogle Scholar
  37. 37.
    Yuede CM, Lee H, Restivo JL, Davis TA, Hettinger JC, Wallace CE, Young KL, Hayne MR et al (2016) Rapid in vivo measurement of beta-amyloid reveals biphasic clearance kinetics in an Alzheimer’s mouse model. J Exp Med 213(5):677–685.  https://doi.org/10.1084/jem.20151428 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Janssen L, Keppens C, De Deyn PP, Van Dam D (2016) Late age increase in soluble amyloid-beta levels in the APP23 mouse model despite steady-state levels of amyloid-beta-producing proteins. Biochim Biophys Acta 1862(1):105–112.  https://doi.org/10.1016/j.bbadis.2015.10.027 CrossRefPubMedGoogle Scholar
  39. 39.
    Schieb H, Kratzin H, Jahn O, Mobius W, Rabe S, Staufenbiel M, Wiltfang J, Klafki HW (2011) Beta-amyloid peptide variants in brains and cerebrospinal fluid from amyloid precursor protein (APP) transgenic mice: comparison with human Alzheimer amyloid. J Biol Chem 286(39):33747–33758.  https://doi.org/10.1074/jbc.M111.246561 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Shin RW, Ogino K, Kondo A, Saido TC, Trojanowski JQ, Kitamoto T, Tateishi J (1997) Amyloid beta-protein (Abeta) 1-40 but not Abeta1-42 contributes to the experimental formation of Alzheimer disease amyloid fibrils in rat brain. J Neurosci 17(21):8187–8193CrossRefGoogle Scholar
  41. 41.
    Ahmed T, Enam SA, Gilani AH (2010) Curcuminoids enhance memory in an amyloid-infused rat model of Alzheimer’s disease. Neuroscience 169(3):1296–1306.  https://doi.org/10.1016/j.neuroscience.2010.05.078 CrossRefPubMedGoogle Scholar
  42. 42.
    Bie B, Zhu W, Pan ZZ (2009) Ethanol-induced delta-opioid receptor modulation of glutamate synaptic transmission and conditioned place preference in central amygdala. Neuroscience 160(2):348–358.  https://doi.org/10.1016/j.neuroscience.2009.02.049 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K (2015) Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138(Pt 6):1738–1755.  https://doi.org/10.1093/brain/awv081 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Wu J, Hocevar M, Foss JF, Bihua Bie B, Naguib M (2017) Activation of CB2 receptor system restores cognitive capacity and hippocampal Sox2 expression in a transgenic mouse model of Alzheimer’s disease. Eur J Pharmacol 811:12–20.  https://doi.org/10.1016/j.ejphar.2017.05.044 CrossRefPubMedGoogle Scholar
  45. 45.
    Bie B, Brown DL, Naguib M (2011) Increased synaptic GluR1 subunits in the anterior cingulate cortex of rats with peripheral inflammation. Eur J Pharmacol 653(1–3):26–31.  https://doi.org/10.1016/j.ejphar.2010.11.027 CrossRefPubMedGoogle Scholar
  46. 46.
    Peritz T, Zeng F, Kannanayakal TJ, Kilk K, Eiriksdottir E, Langel U, Eberwine J (2006) Immunoprecipitation of mRNA-protein complexes. Nat Protoc 1(2):577–580.  https://doi.org/10.1038/nprot.2006.82 CrossRefPubMedGoogle Scholar
  47. 47.
    Bie B, Peng Y, Zhang Y, Pan ZZ (2005) cAMP-mediated mechanisms for pain sensitization during opioid withdrawal. J Neurosci 25(15):3824–3832.  https://doi.org/10.1523/JNEUROSCI.5010-04.2005 CrossRefPubMedGoogle Scholar
  48. 48.
    Zhang M, Wang Q, Huang Y (2007) Fragile X mental retardation protein FMRP and the RNA export factor NXF2 associate with and destabilize Nxf1 mRNA in neuronal cells. Proc Natl Acad Sci U S A 104(24):10057–10062.  https://doi.org/10.1073/pnas.0700169104 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Li Y, Stockton ME, Bhuiyan I, Eisinger BE, Gao Y, Miller JL, Bhattacharyya A, Zhao X (2016) MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome. Sci Transl Med 8(336):336ra361.  https://doi.org/10.1126/scitranslmed.aad9370 CrossRefGoogle Scholar
  50. 50.
    Bie B, Zhu W, Pan ZZ (2009) Rewarding morphine-induced synaptic function of delta-opioid receptors on central glutamate synapses. J Pharmacol Exp Ther 329(1):290–296.  https://doi.org/10.1124/jpet.108.148908 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Michailidou I, Willems JG, Kooi EJ, van Eden C, Gold SM, Geurts JJ, Baas F, Huitinga I et al (2015) Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus. Ann Neurol 77(6):1007–1026.  https://doi.org/10.1002/ana.24398 CrossRefPubMedGoogle Scholar
  52. 52.
    Perry VH, Nicoll JAR, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6(4):193–201CrossRefGoogle Scholar
  53. 53.
    Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A et al (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 17(3):400–406.  https://doi.org/10.1038/nn.3641 CrossRefPubMedGoogle Scholar
  54. 54.
    Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29(13):3974–3980.  https://doi.org/10.1523/JNEUROSCI.4363-08.2009 CrossRefPubMedGoogle Scholar
  55. 55.
    Brown GC, Neher JJ (2014) Microglial phagocytosis of live neurons. Nat Rev Neurosci 15(4):209–216.  https://doi.org/10.1038/nrn3710 CrossRefPubMedGoogle Scholar
  56. 56.
    Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM et al (2010) Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13(4):411–413.  https://doi.org/10.1038/nn.2511 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Kokiko-Cochran O, Ransohoff L, Veenstra M, Lee S, Saber M, Sikora M, Teknipp R, Xu G et al (2016) Altered neuroinflammation and behavior after traumatic brain injury in a mouse model of Alzheimer’s disease. J Neurotrauma 33(7):625–640.  https://doi.org/10.1089/neu.2015.3970 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Webster SJ, Van Eldik LJ, Watterson DM, Bachstetter AD (2015) Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment. J Neurosci 35(16):6554–6569.  https://doi.org/10.1523/JNEUROSCI.0291-15.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Lalonde R, Kim HD, Maxwell JA, Fukuchi K (2005) Exploratory activity and spatial learning in 12-month-old APP(695)SWE/co+PS1/DeltaE9 mice with amyloid plaques. Neurosci Lett 390(2):87–92.  https://doi.org/10.1016/j.neulet.2005.08.028 CrossRefPubMedGoogle Scholar
  60. 60.
    Volianskis A, Kostner R, Molgaard M, Hass S, Jensen MS (2010) Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1deltaE9-deleted transgenic mice model of ss-amyloidosis. Neurobiol Aging 31(7):1173–1187.  https://doi.org/10.1016/j.neurobiolaging.2008.08.005 CrossRefPubMedGoogle Scholar
  61. 61.
    Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I et al (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4(1):97–100CrossRefGoogle Scholar
  62. 62.
    Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O (2004) Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 114(11):1624–1634.  https://doi.org/10.1172/JCI22831 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Montarolo F, Parolisi R, Hoxha E, Boda E, Tempia F (2013) Early enriched environment exposure protects spatial memory and accelerates amyloid plaque formation in APP(Swe)/PS1(L166P) mice. PLoS One 8(7):e69381.  https://doi.org/10.1371/journal.pone.0069381 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Viana da Silva S, Haberl MG, Zhang P, Bethge P, Lemos C, Goncalves N, Gorlewicz A, Malezieux M et al (2016) Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors. Nat Commun 7:11915.  https://doi.org/10.1038/ncomms11915 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131(6):1164–1178.  https://doi.org/10.1016/j.cell.2007.10.036 CrossRefPubMedGoogle Scholar
  66. 66.
    Takano M, Kawabata S, Komaki Y, Shibata S, Hikishima K, Toyama Y, Okano H, Nakamura M (2014) Inflammatory cascades mediate synapse elimination in spinal cord compression. J Neuroinflammation 11:40.  https://doi.org/10.1186/1742-2094-11-40 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Zhang Z, Pinto AM, Wan L, Wang W, Berg MG, Oliva I, Singh LN, Dengler C et al (2013) Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc Natl Acad Sci U S A 110(48):19348–19353.  https://doi.org/10.1073/pnas.1319280110 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Chu Y, Jin X, Parada I, Pesic A, Stevens B, Barres B, Prince DA (2010) Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc Natl Acad Sci U S A 107(17):7975–7980.  https://doi.org/10.1073/pnas.0913449107 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Shen Y, Li R, McGeer EG, McGeer PL (1997) Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res 769(2):391–395CrossRefGoogle Scholar
  70. 70.
    Fischer B, Schmoll H, Riederer P, Bauer J, Platt D, Popa-Wagner A (1995) Complement C1q and C3 mRNA expression in the frontal cortex of Alzheimer’s patients. J Mol Med (Berl) 73(9):465–471CrossRefGoogle Scholar
  71. 71.
    Matsuda K, Budisantoso T, Mitakidis N, Sugaya Y, Miura E, Kakegawa W, Yamasaki M, Konno K et al (2016) Transsynaptic modulation of kainate receptor functions by C1q-like proteins. Neuron 90(4):752–767.  https://doi.org/10.1016/j.neuron.2016.04.001 CrossRefPubMedGoogle Scholar
  72. 72.
    Rostami E, Davidsson J, Gyorgy A, Agoston DV, Risling M, Bellander BM (2013) The terminal pathway of the complement system is activated in focal penetrating but not in mild diffuse traumatic brain injury. J Neurotrauma 30(23):1954–1965.  https://doi.org/10.1089/neu.2012.2583 CrossRefPubMedGoogle Scholar
  73. 73.
    Schafer MK, Schwaeble WJ, Post C, Salvati P, Calabresi M, Sim RB, Petry F, Loos M et al (2000) Complement C1q is dramatically up-regulated in brain microglia in response to transient global cerebral ischemia. J Immunol 164(10):5446–5452CrossRefGoogle Scholar
  74. 74.
    Zipfel PF, Skerka C (2009) Complement regulators and inhibitory proteins. Nat Rev Immunol 9(10):729–740.  https://doi.org/10.1038/nri2620 CrossRefPubMedGoogle Scholar
  75. 75.
    Ceman S, O'Donnell WT, Reed M, Patton S, Pohl J, Warren ST (2003) Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet 12(24):3295–3305.  https://doi.org/10.1093/hmg/ddg350 CrossRefPubMedGoogle Scholar
  76. 76.
    Martin HGS, Lassalle O, Brown JT, Manzoni OJ (2016) Age-dependent long-term potentiation deficits in the prefrontal cortex of the Fmr1 knockout mouse model of fragile X syndrome. Cereb Cortex 26(5):2084–2092.  https://doi.org/10.1093/cercor/bhv031 CrossRefPubMedGoogle Scholar
  77. 77.
    Sokol DK, Maloney B, Long JM, Ray B, Lahiri DK (2011) Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links. Neurology 76(15):1344–1352.  https://doi.org/10.1212/WNL.0b013e3182166dc7 CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Lee EK, Kim HH, Kuwano Y, Abdelmohsen K, Srikantan S, Subaran SS, Gleichmann M, Mughal MR et al (2010) hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nat Struct Mol Biol 17(6):732–739.  https://doi.org/10.1038/nsmb.1815 CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Ronesi JA, Huber KM (2008) Metabotropic glutamate receptors and fragile x mental retardation protein: partners in translational regulation at the synapse. Sci Signal 1(5):pe6.  https://doi.org/10.1126/stke.15pe6 CrossRefPubMedGoogle Scholar
  80. 80.
    Kim SH, Steele JW, Lee SW, Clemenson GD, Carter TA, Treuner K, Gadient R, Wedel P et al (2014) Proneurogenic group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Abeta oligomer mouse. Mol Psychiatry.  https://doi.org/10.1038/mp.2014.87
  81. 81.
    Lavreysen H, Wouters R, Bischoff F, Nobrega Pereira S, Langlois X, Blokland S, Somers M, Dillen L et al (2004) JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist. Neuropharmacology 47(7):961–972.  https://doi.org/10.1016/j.neuropharm.2004.08.007 CrossRefPubMedGoogle Scholar
  82. 82.
    Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322.  https://doi.org/10.1146/annurev.pharmtox.011008.145533 CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Anesthesiology InstituteCleveland ClinicClevelandUSA
  2. 2.Cleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandUSA

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