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Microglia emerge as central players in brain disease

Abstract

There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

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Figure 1: Ontogeny of microglia and physiological roles in CNS development, homeostasis, and plasticity.

Debbie Maizels/Springer Nature

Figure 2: Microglia states in health and disease.

Debbie Maizels/Springer Nature

Figure 3: Microglia–neuron interactions in the spinal cord are crucial to pain hypersensitivity induced by peripheral-nerve injury in males.

Debbie Maizels/Springer Nature

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References

  1. Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).

    Article  PubMed  CAS  Google Scholar 

  4. Sheng, J., Ruedl, C. & Karjalainen, K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43, 382–393 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hagemeyer, N. et al. Transcriptome-based profiling of yolk sac-derived macrophages reveals a role for Irf8 in macrophage maturation. EMBO J. 35, 1730–1744 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Minten, C., Terry, R., Deffrasnes, C., King, N.J. & Campbell, I.L. IFN regulatory factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS. PLoS One 7, e49851 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).

    Article  PubMed  CAS  Google Scholar 

  11. Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pannell, M. et al. The subpopulation of microglia expressing functional muscarinic acetylcholine receptors expands in stroke and Alzheimer's disease. Brain Struct. Funct. 221, 1157–1172 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Wlodarczyk, A. et al. Pathologic and protective roles for microglial subsets and bone marrow- and blood-derived myeloid cells in central nervous system inflammation. Front. Immunol. 6, 463 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Lawson, L.J., Perry, V.H. & Gordon, S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48, 405–415 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Erblich, B., Zhu, L., Etgen, A.M., Dobrenis, K. & Pollard, J.W. Absence of colony stimulating factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS One 6, e26317 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Greter, M. et al. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36, 1031–1046 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Elmore, M.R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Salter, M.W. & Beggs, S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15–24 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Tay, T.L., Savage, J., Hui, C.W., Bisht, K. & Tremblay, M.E. Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J. Physiol. (Lond.) 595, 1929–1945 (2016).

    Article  CAS  Google Scholar 

  22. Hong, S., Dissing-Olesen, L. & Stevens, B. New insights on the role of microglia in synaptic pruning in health and disease. Curr. Opin. Neurobiol. 36, 128–134 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Abiega, O. et al. Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling. PLoS Biol. 14, e1002466 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Li, Y., Du, X.F., Liu, C.S., Wen, Z.L. & Du, J.L. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev. Cell 23, 1189–1202 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Fontainhas, A.M. et al. Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLoS One 6, e15973 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Eyo, U.B. et al. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J. Neurosci. 34, 10528–10540 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Dissing-Olesen, L. et al. Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth. J. Neurosci. 34, 10511–10527 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Tremblay, M.E., Lowery, R.L. & Majewska, A.K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Schafer, D.P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Paolicelli, R.C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. van Lookeren Campagne, M., Wiesmann, C. & Brown, E.J. Macrophage complement receptors and pathogen clearance. Cell. Microbiol. 9, 2095–2102 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Marín-Teva, J.L., Cuadros, M.A., Martín-Oliva, D. & Navascués, J. Microglia and neuronal cell death. Neuron Glia Biol. 7, 25–40 (2011).

    Article  PubMed  Google Scholar 

  38. Brown, G.C. & Neher, J.J. Microglial phagocytosis of live neurons. Nat. Rev. Neurosci. 15, 209–216 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Marín-Teva, J.L. et al. Microglia promote the death of developing Purkinje cells. Neuron 41, 535–547 (2004).

    Article  PubMed  Google Scholar 

  41. Frade, J.M. & Barde, Y.A. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20, 35–41 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Sedel, F., Béchade, C., Vyas, S. & Triller, A. Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death. J. Neurosci. 24, 2236–2246 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wakselman, S. et al. Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J. Neurosci. 28, 8138–8143 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Schafer, D.P. & Stevens, B. Microglia function in central nervous system development and plasticity. Cold Spring Harb. Perspect. Biol. 7, a020545 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Pascual, O., Ben Achour, S., Rostaing, P., Triller, A. & Bessis, A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc. Natl. Acad. Sci. USA 109, E197–E205 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Bliss, T.V., Collingridge, G.L. & Morris, R.G. Synaptic plasticity in health and disease: introduction and overview. Phil. Trans. R. Soc. Lond. B 369, 20130129 (2013).

    Article  Google Scholar 

  47. Zhao, C., Deng, W. & Gage, F.H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Akers, K.G. et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science 344, 598–602 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Rogers, J.T. et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J. Neurosci. 31, 16241–16250 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schafer, D.P., Lehrman, E.K. & Stevens, B. The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61, 24–36 (2013).

    Article  PubMed  Google Scholar 

  51. Koeglsperger, T. et al. Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-b1 in the CNS. Glia 61, 985–1002 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  52. George, J., Cunha, R.A., Mulle, C. & Amédée, T. Microglia-derived purines modulate mossy fibre synaptic transmission and plasticity through P2X4 and A1 receptors. Eur. J. Neurosci. 43, 1366–1378 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Sipe, G.O. et al. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat. Commun. 7, 10905 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sierra, A. et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483–495 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bachstetter, A.D. et al. Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol. Aging 32, 2030–2044 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Gemma, C. & Bachstetter, A.D. The role of microglia in adult hippocampal neurogenesis. Front. Cell. Neurosci. 7, 229 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Tremblay, M.E. et al. The role of microglia in the healthy brain. J. Neurosci. 31, 16064–16069 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Parkhurst, C.N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Butovsky, O. et al. Identification of a unique TGF-b-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Sierra, A. et al. The “Big-Bang” for modern glial biology: Translation and comments on Pío del Río-Hortega 1919 series of papers on microglia. Glia 64, 1801–1840 (2016).

    Article  PubMed  Google Scholar 

  61. Murray, P.J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ransohoff, R.M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Chiu, I.M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Reports 4, 385–401 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Holtman, I.R. et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol. Commun. 3, 31 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Pardo, C.A., Vargas, D.L. & Zimmerman, A.W. Immunity, neuroglia and neuroinflammation in autism. Int. Rev. Psychiatry 17, 485–495 (2005).

    Article  PubMed  Google Scholar 

  66. Morgan, J.T. et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol. Psychiatry 68, 368–376 (2010).

    Article  PubMed  Google Scholar 

  67. Vargas, D.L., Nascimbene, C., Krishnan, C., Zimmerman, A.W. & Pardo, C.A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57, 67–81 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Tetreault, N.A. et al. Microglia in the cerebral cortex in autism. J. Autism Dev. Disord. 42, 2569–2584 (2012).

    Article  PubMed  Google Scholar 

  69. Gupta, S. et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5, 5748 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Suzuki, K. et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70, 49–58 (2013).

    Article  PubMed  Google Scholar 

  71. Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Schafer, D.P. et al. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. eLife 5, e15224 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Derecki, N.C. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Maezawa, I. & Jin, L.W. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J. Neurosci. 30, 5346–5356 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Estes, M.L. & McAllister, A.K. Maternal immune activation: Implications for neuropsychiatric disorders. Science 353, 772–777 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Giovanoli, S. et al. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science 339, 1095–1099 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Patterson, P.H. Maternal infection and immune involvement in autism. Trends Mol. Med. 17, 389–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Garay, P.A., Hsiao, E.Y., Patterson, P.H. & McAllister, A.K. Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav. Immun. 31, 54–68 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Squarzoni, P. et al. Microglia modulate wiring of the embryonic forebrain. Cell Reports 8, 1271–1279 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Penzes, P., Cahill, M.E., Jones, K.A., VanLeeuwen, J.E. & Woolfrey, K.M. Dendritic spine pathology in neuropsychiatric disorders. Nat. Neurosci. 14, 285–293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Feinberg, I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J. Psychiatr. Res. 17, 319–334 (1982–83).

    Article  PubMed  Google Scholar 

  82. Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Chen, S.K. et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775–785 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Paloneva, J. et al. CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts. Neurology 56, 1552–1558 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Bianchin, M.M. et al. Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy–PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Cell. Mol. Neurobiol. 24, 1–24 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. McCarthy, M.M. Multifaceted origins of sex differences in the brain. Phil. Trans. R. Soc. Lond. B 371, 20150106 (2016).

    Article  CAS  Google Scholar 

  87. Bolton, J.L. et al. Gestational exposure to air pollution alters cortical volume, microglial morphology, and microglia–Neuron interactions in a sex-specific manner. Front. Synaptic Neurosci. 9, 10 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Hanamsagar, R. et al. Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. Glia 65, 1504–1520 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Hanamsagar, R. & Bilbo, S.D. Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development. J. Steroid Biochem. Mol. Biol. 160, 127–133 (2016).

    Article  CAS  PubMed  Google Scholar 

  90. Wyss-Coray, T. & Rogers, J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb. Perspect. Med. 2, a006346 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Lambert, J.C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707–720 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Efthymiou, A.G. & Goate, A.M. Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener. 12, 43 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Villegas-Llerena, C., Phillips, A., Garcia-Reitboeck, P., Hardy, J. & Pocock, J.M. Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease. Curr. Opin. Neurobiol. 36, 74–81 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. Colonna, M. & Wang, Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 17, 201–207 (2016).

    Article  CAS  PubMed  Google Scholar 

  98. Suárez-Calvet, M. et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers. EMBO Mol. Med. 8, 466–476 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Colonna, M. TREMs in the immune system and beyond. Nat. Rev. Immunol. 3, 445–453 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Kleinberger, G. et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 36, 1837–1853 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ulrich, J.D. et al. Altered microglial response to Ab plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Jay, T.R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212, 287–295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Jay, T.R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease. J. Neurosci. 37, 637–647 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Atagi, Y. et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043–26050 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yeh, F.L., Wang, Y., Tom, I., Gonzalez, L.C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91, 328–340 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med. 6, 243ra86 (2014).

    Article  PubMed  CAS  Google Scholar 

  108. Suárez-Calvet, M. et al. Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. Sci. Transl. Med. 8, 369ra178 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Paloneva, J. et al. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat. Genet. 25, 357–361 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Paloneva, J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71, 656–662 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Griciuc, A. et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bertram, L. et al. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 83, 623–632 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jun, G. et al. Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch. Neurol. 67, 1473–1484 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Fonseca, M.I. et al. Analysis of the putative role of CR1 in Alzheimer's disease: genetic association, expression and function. PLoS One 11, e0149792 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Terry, R.D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

    Article  CAS  PubMed  Google Scholar 

  116. DeKosky, S.T., Scheff, S.W. & Styren, S.D. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5, 417–421 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Stephan, A.H., Barres, B.A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Howell, G.R. et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J. Clin. Invest. 121, 1429–1444 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Williams, P.A. et al. Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol. Neurodegener. 11, 26 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Vasek, M.J. et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zamanian, J.L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sofroniew, M.V. & Vinters, H.V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).

    Article  PubMed  Google Scholar 

  124. Clarke, L.E. & Barres, B.A. Emerging roles of astrocytes in neural circuit development. Nat. Rev. Neurosci. 14, 311–321 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Chung, W.S., Allen, N.J. & Eroglu, C. Astrocytes control synapse formation, function, and elimination. Cold Spring Harb. Perspect. Biol. 7, a020370 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Liddelow, S.A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Chung, W.S., Welsh, C.A., Barres, B.A. & Stevens, B. Do glia drive synaptic and cognitive impairment in disease? Nat. Neurosci. 18, 1539–1545 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Iaccarino, H.F. et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Beggs, S., Trang, T. & Salter, M.W. P2X4R+ microglia drive neuropathic pain. Nat. Neurosci. 15, 1068–1073 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Sorge, R.E. et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat. Med. 18, 595–599 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Masuda, T. et al. Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat. Commun. 7, 12529 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. North, R.A. P2X receptors. Phil. Trans. R. Soc. Lond. B 371, 20150427 (2016).

    Article  CAS  Google Scholar 

  133. Tozaki-Saitoh, H. et al. P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J. Neurosci. 28, 4949–4956 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Burnstock, G. Purinergic mechanisms and pain. Adv. Pharmacol. 75, 91–137 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Masuda, T. et al. Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. Nat. Commun. 5, 3771 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Masuda, T. et al. IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Reports 1, 334–340 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003).

    Article  CAS  PubMed  Google Scholar 

  139. Sorge, R.E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Ferrini, F. et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl homeostasis. Nat. Neurosci. 16, 183–192 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Macosko, E.Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169, 1276–1290.e17 (2017).

    Article  CAS  PubMed  Google Scholar 

  143. Pandya, H. et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat. Neurosci. 20, 753–759 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Muffat, J. et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat. Med. 22, 1358–1367 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Hammond, T.R. & Stevens, B. Increasing the neurological-disease toolbox using iPSC-derived microglia. Nat. Med. 22, 1206–1207 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. Bohlen, C.J. et al. Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759–773.e8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Choi, S.H. et al. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature 515, 274–278 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Abud, E.M. et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94, 278–293.e9 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Bennett, M.L. et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. USA 113, E1738–E1746 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Coull, J.A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Hildebrand, M.E. et al. Potentiation of synaptic GluN2B NMDAR currents by Fyn kinase is gated through BDNF-mediated disinhibition in spinal pain processing. Cell Reports 17, 2753–2765 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Hodgkin, J. Sex determination and the generation of sexually dimorphic nervous systems. Neuron 6, 177–185 (1991).

    Article  CAS  PubMed  Google Scholar 

  154. Chowen, J.A., Azcoitia, I., Cardona-Gomez, G.P. & Garcia-Segura, L.M. Sex steroids and the brain: lessons from animal studies. J. Pediatr. Endocrinol. Metab. 13, 1045–1066 (2000).

    Article  CAS  PubMed  Google Scholar 

  155. Gill, S.K., Bhattacharya, M., Ferguson, S.S. & Rylett, R.J. Identification of a novel nuclear localization signal common to 69- and 82-kDa human choline acetyltransferase. J. Biol. Chem. 278, 20217–20224 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Schwarz, J.M., Sholar, P.W. & Bilbo, S.D. Sex differences in microglial colonization of the developing rat brain. J. Neurochem. 120, 948–963 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Acaz-Fonseca, E., Duran, J.C., Carrero, P., Garcia-Segura, L.M. & Arevalo, M.A. Sex differences in glia reactivity after cortical brain injury. Glia 63, 1966–1981 (2015).

    Article  PubMed  Google Scholar 

  158. McCullough, L.D. et al. Stroke sensitivity in the aged: sex chromosome complement vs. gonadal hormones. Aging (Albany. NY) 8, 1432–1441 (2016).

    Article  CAS  Google Scholar 

  159. Bollinger, J.L., Bergeon Burns, C.M. & Wellman, C.L. Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. Brain Behav. Immun. 52, 88–97 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Arevalo, M.A., Santos-Galindo, M., Acaz-Fonseca, E., Azcoitia, I. & Garcia-Segura, L.M. Gonadal hormones and the control of reactive gliosis. Horm. Behav. 63, 216–221 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Lenz, K.M., Nugent, B.M., Haliyur, R. & McCarthy, M.M. Microglia are essential to masculinization of brain and behavior. J. Neurosci. 33, 2761–2772 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Stellwagen, D. & Malenka, R.C. Synaptic scaling mediated by glial TNF-a. Nature 440, 1054–1059 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Shi, Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl. Med. 9, eaaf6295 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Fonseca, M.I. et al. Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease. J. Neuroinflammation 8, 4 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Fonseca, M.I., Zhou, J., Botto, M. & Tenner, A.J. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J. Neurosci. 24, 6457–6465 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank A. Sengar (Hospital for Sick Children) for important discussions about the review and assistance with the manuscript and figures. Work of the authors is supported by CIHR, Brain Canada, Krembil Foundation (M.W.S.) and NIH, NIH RO1NS071008 (B.S.), Simons Foundation SFARi (B.S.). M.W.S. holds the Northbridge Chair in Paediatric Research at the Hospital for Sick Children.

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Salter, M., Stevens, B. Microglia emerge as central players in brain disease. Nat Med 23, 1018–1027 (2017). https://doi.org/10.1038/nm.4397

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