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Cited by 185

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Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling

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Abiega, Oihane, Beccari, Sol, Diaz-Aparicio, Irune, Nadjar, Agnes, Layé, Sophie, Leyrolle, Quentin, Gómez-Nicola, Diego, Domercq, María, Pérez-Samartín, Alberto, Sánchez-Zafra, Víctor, Paris, Iñaki, Valero, Jorge, Savage, Julie C., Hui, Chin-Wai, Tremblay, Marie-Ève, Deudero, Juan J. P., Brewster, Amy L., Anderson, Anne E., Zaldumbide, Laura, Galbarriatu, Lara, Marinas, Ainhoa, Vivanco, Maria dM., Matute, Carlos, Maletic-Savatic, Mirjana, Encinas, Juan M., Sierra, Amanda·2016·PLOS Biology
DOI 10.1371/journal.pbio.1002466
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Abstract

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.

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Research works printed but not linked: 64

  1. ME Tremblay, 2011, The role of microglia in the healthy brain, J Neurosci, 31, 16064, 10.1523/JNEUROSCI.4158-11.2011 · DOI · Paper page
  2. DP Schafer, 2013, The "quad-partite" synapse: microglia-synapse interactions in the developing and mature CNS, Glia, 61, 24, 10.1002/glia.22389 · DOI · Paper page
  3. AM Casano, 2015, Microglia: multitasking specialists of the brain, Developmental cell, 32, 469, 10.1016/j.devcel.2015.01.018 · DOI · Paper page
  4. R Mingam, 2008, Uncoupling of interleukin-6 from its signalling pathway by dietary n-3-polyunsaturated fatty acid deprivation alters sickness behaviour in mice, Eur J Neurosci, 28, 1877, 10.1111/j.1460-9568.2008.06470.x · DOI
  5. RJ Racine, 1972, Modification of seizure activity by electrical stimulation. II. Motor seizure, Electroencephalography and clinical neurophysiology, 32, 281, 10.1016/0013-4694(72)90177-0 · DOI · Paper page
  6. A Sierra, 2015, Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis, Cell Stem Cell, 16, 488, 10.1016/j.stem.2015.04.003 · DOI · Paper page
  7. T Magnus, 2002, Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: implications for the role of glial cells in the inflamed central nervous system, J Neuropathol Exp Neurol, 61, 760, 10.1093/jnen/61.9.760 · DOI
  8. Z Lu, 2011, Phagocytic activity of neuronal progenitors regulates adult neurogenesis, Nat Cell Biol, 13, 1076, 10.1038/ncb2299 · DOI · Paper page
  9. LS Overstreet, 2004, A transgenic marker for newly born granule cells in dentate gyrus, J Neurosci, 24, 3251, 10.1523/JNEUROSCI.5173-03.2004 · DOI · Paper page
  10. PA Hall, 1990, Immunohistochemical markers of cellular proliferation: achievements, problems and prospects, Cell and tissue kinetics, 23, 505
  11. NV Serbina, 2006, Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2, Nature immunology, 7, 311, 10.1038/ni1309 · DOI · Paper page
  12. D Gomez-Nicola, 2014, Differential role of CCR2 in the dynamics of microglia and perivascular macrophages during prion disease, Glia, 62, 1041, 10.1002/glia.22660 · DOI
  13. P Dibaj, 2010, Long-lasting post-mortem activity of spinal microglia in situ in mice, Journal of neuroscience research, 88, 2431, 10.1002/jnr.22402 · DOI
  14. S Rotshenker, 2003, Microglia and macrophage activation and the regulation of complement-receptor-3 (CR3/MAC-1)-mediated myelin phagocytosis in injury and disease, Journal of molecular neuroscience: MN, 21, 65, 10.1385/JMN:21:1:65 · DOI
  15. J Preissler, 2015, Altered microglial phagocytosis in GPR34-deficient mice, Glia, 63, 206, 10.1002/glia.22744 · DOI
  16. K Ohsawa, 2007, Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis, Glia, 55, 604, 10.1002/glia.20489 · DOI · Paper page
  17. S Koizumi, 2007, UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis, Nature, 446, 1091, 10.1038/nature05704 · DOI · Paper page
  18. C Madore, 2013, Early morphofunctional plasticity of microglia in response to acute lipopolysaccharide, Brain Behav Immun, 34, 151, 10.1016/j.bbi.2013.08.008 · DOI
  19. N Dale, 2009, Release of adenosine and ATP during ischemia and epilepsy, Curr Neuropharmacol, 7, 160, 10.2174/157015909789152146 · DOI · Paper page
  20. MF Santiago, 2011, Targeting pannexin1 improves seizure outcome, PLoS ONE, 6, e25178, 10.1371/journal.pone.0025178 · DOI · Paper page
  21. X Wang, 2004, P2X7 receptor inhibition improves recovery after spinal cord injury, Nat Med, 10, 821, 10.1038/nm1082 · DOI · Paper page
  22. SD Skaper, 2010, The P2X7 purinergic receptor: from physiology to neurological disorders, FASEB J, 24, 337, 10.1096/fj.09-138883 · DOI · Paper page
  23. FB Chekeni, 2010, Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis, Nature, 467, 863, 10.1038/nature09413 · DOI · Paper page
  24. CT Ekdahl, 2001, Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus, Eur J Neurosci, 14, 937, 10.1046/j.0953-816x.2001.01713.x · DOI
  25. CT Ekdahl, 2003, Death mechanisms in status epilepticus-generated neurons and effects of additional seizures on their survival, Neurobiol Dis, 14, 513, 10.1016/j.nbd.2003.08.022 · DOI
  26. A Tashiro, 2006, NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus, Nature, 442, 929, 10.1038/nature05028 · DOI · Paper page
  27. JM Encinas, 2011, Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus, Cell Stem Cell, 8, 566, 10.1016/j.stem.2011.03.010 · DOI · Paper page
  28. M Dragunow, 1989, The use of c-fos as a metabolic marker in neuronal pathway tracing, Journal of neuroscience methods, 29, 261, 10.1016/0165-0270(89)90150-7 · DOI · Paper page
  29. R De Simone, 2003, Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells, J Neuropathol Exp Neurol, 62, 208, 10.1093/jnen/62.2.208 · DOI
  30. H Kettenmann, 2007, Neuroscience: the brain's garbage men, Nature, 446, 987, 10.1038/nature05713 · DOI
  31. LJ Wu, 2008, Resting microglial motility is independent of synaptic plasticity in mammalian brain, J Neurophysiol, 99, 2026, 10.1152/jn.01210.2007 · DOI
  32. RN Christensen, 2006, Kainate induces rapid redistribution of the actin cytoskeleton in ameboid microglia, Journal of neuroscience research, 84, 170, 10.1002/jnr.20865 · DOI
  33. AM Kaindl, 2012, Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain, Ann Neurol, 72, 536, 10.1002/ana.23626 · DOI · Paper page
  34. K Beppu, 2013, Expression, subunit composition, and function of AMPA-type glutamate receptors are changed in activated microglia; possible contribution of GluA2 (GluR-B)-deficiency under pathological conditions, Glia, 61, 881, 10.1002/glia.22481 · DOI
  35. M Domercq, 2013, Neurotransmitter signaling in the pathophysiology of microglia, Front Cell Neurosci, 7, 49
  36. UB Eyo, 2014, Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus, J Neurosci, 34, 10528, 10.1523/JNEUROSCI.0416-14.2014 · DOI · Paper page
  37. L Dissing-Olesen, 2014, Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth, J Neurosci, 34, 10511, 10.1523/JNEUROSCI.0405-14.2014 · DOI · Paper page
  38. A Heinrich, 2012, K+ depolarization evokes ATP, adenosine and glutamate release from glia in rat hippocampus: a microelectrode biosensor study, British journal of pharmacology, 167, 1003, 10.1111/j.1476-5381.2012.01932.x · DOI
  39. MR Elliott, 2009, Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance, Nature, 461, 282, 10.1038/nature08296 · DOI · Paper page
  40. E Avignone, 2008, Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling, J Neurosci, 28, 9133, 10.1523/JNEUROSCI.1820-08.2008 · DOI · Paper page
  41. L Ulmann, 2013, Involvement of P2X4 receptors in hippocampal microglial activation after status epilepticus, Glia, 61, 1306, 10.1002/glia.22516 · DOI
  42. D Park, 2011, Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein, Nature, 477, 220, 10.1038/nature10340 · DOI · Paper page
  43. E Avignone, 2015, Altered morphological dynamics of activated microglia after induction of status epilepticus, Journal of neuroinflammation, 12, 202, 10.1186/s12974-015-0421-6 · DOI
  44. Y Xu, 2012, Altered expression of CX3CL1 in patients with epilepsy and in a rat model, The American journal of pathology, 180, 1950, 10.1016/j.ajpath.2012.01.024 · DOI
  45. RC Paolicelli, 2014, Fractalkine regulation of microglial physiology and consequences on the brain and behavior, Front Cell Neurosci, 8, 129, 10.3389/fncel.2014.00129 · DOI · Paper page
  46. BE Alger, 2014, Seizing an opportunity for the endocannabinoid system, Epilepsy, 14, 272
  47. T Bisogno, 2010, Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders, CNS & neurological disorders drug targets, 9, 564, 10.2174/187152710793361568 · DOI · Paper page
  48. J Otahal, 2014, Epileptic focus and alteration of metabolism, International review of neurobiology, 114, 209, 10.1016/B978-0-12-418693-4.00009-1 · DOI
  49. G Zsurka, 2015, Mitochondrial dysfunction and seizures: the neuronal energy crisis, The Lancet Neurology, 14, 956, 10.1016/S1474-4422(15)00148-9 · DOI · Paper page
  50. TC Hornik, 2014, Inflammation induces multinucleation of Microglia via PKC inhibition of cytokinesis, generating highly phagocytic multinucleated giant cells, J Neurochem, 128, 650, 10.1111/jnc.12477 · DOI
  51. J Savill, 2002, A blast from the past: clearance of apoptotic cells regulates immune responses, Nature reviews Immunology, 2, 965, 10.1038/nri957 · DOI · Paper page
  52. A Vezzani, 1999, Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures, J Neurosci, 19, 5054, 10.1523/JNEUROSCI.19-12-05054.1999 · DOI · Paper page
  53. A Vezzani, 2011, The role of inflammation in epilepsy, Nat Rev Neurol, 7, 31, 10.1038/nrneurol.2010.178 · DOI · Paper page
  54. AA Kan, 2012, Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response, Cellular and molecular life sciences: CMLS, 69, 3127, 10.1007/s00018-012-0992-7 · DOI · Paper page
  55. JK Kleen, 2010, Taming TLR4 may ease seizures, Nat Med, 16, 369, 10.1038/nm0410-369 · DOI
  56. A Vezzani, 2011, Therapeutic potential of new antiinflammatory drugs, Epilepsia, 52, 67, 10.1111/j.1528-1167.2011.03242.x · doi:10.1111/j.1528-1167.2011.03242.x
  57. L Zhuo, 1997, Live astrocytes visualized by green fluorescent protein in transgenic mice, Dev Biol, 187, 36, 10.1006/dbio.1997.8601 · DOI · Paper page
  58. JL Mignone, 2004, Neural stem and progenitor cells in nestin-GFP transgenic mice, J Comp Neurol, 469, 311, 10.1002/cne.10964 · DOI · Paper page
  59. V Bouilleret, 1999, Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy, Neuroscience, 89, 717, 10.1016/S0306-4522(98)00401-1 · DOI · Paper page
  60. S Moussaud, 2010, A new method to isolate microglia from adult mice and culture them for an extended period of time, Journal of neuroscience methods, 187, 243, 10.1016/j.jneumeth.2010.01.017 · DOI
  61. MC Hsiao, 2014, An in vitro seizure model from human hippocampal slices using multi-electrode arrays, Journal of neuroscience methods
  62. P Thevenaz, 1998, A pyramid approach to subpixel registration based on intensity, IEEE transactions on image processing: a publication of the IEEE Signal Processing Society, 7, 27, 10.1109/83.650848 · DOI · Paper page
  63. A Parslow, 2014, Sample drift correction following 4D confocal time-lapse imaging, J Vis Exp, 10.3791/51086 · DOI · Paper page
  64. MJ Kwon, 2009, Identification of novel reference genes using multiplatform expression data and their validation for quantitative gene expression analysis, PLoS ONE, 4, e6162, 10.1371/journal.pone.0006162 · DOI

Cited by

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Metadata

Authors
Abiega, O., Beccari, S., Diaz-Aparicio, I., Nadjar, A., Layé, S., Leyrolle, Q., Gómez-Nicola, D., Domercq, M., Pérez-Samartín, A., Sánchez-Zafra, V., Paris, I., Valero, J., Savage, J. C., Hui, C.-W., Tremblay, M.-È., Deudero, J. J. P., Brewster, A. L., Anderson, A. E., Zaldumbide, L., Galbarriatu, L., Marinas, A., Vivanco, M. D., Matute, C., Maletic-Savatic, M., Encinas, J. M., & Sierra, A.
Venue
PLOS Biology
Publisher
Public Library of Science (PLoS)
Published
2016-05-26
Volume
14
Issue
5
Pages
e1002466
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.1002466
OpenAlex
W2402129233
Cited by
185
References
24
FWCI
11.43
Type
journal article
Language
en
Update notices
Open access
gold
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Ministerio de Economía y Competitividad (BFU2012-32089, RYC-2013-12817, SAF2012-40085, RYC-2012-11137, Predoctoral fellowship)
  • Eusko Jaurlaritza (S-PC 12UN014, Predoctoral Fellowship)
  • Ikerbasque, Basque Foundation for Science (Start up)
  • Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-05308)
  • National Institutes of Health (P30HD024064, R01 NS 39943, NIH R01 NS 49427, T32 NS, 43124)
  • Christopher and Dana Reeve Foundation
  • Evelyn F. McKnight Brain Research Foundation
  • Epilepsy Foundation (Postdoctoral Fellowship)
  • Medical Research Council (MR/K022687/1)
  • Euskal Herriko Unibertsitatea (Predoctoral Fellowship)

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