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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Debbie Maizels/Springer Nature

Debbie Maizels/Springer Nature

Debbie Maizels/Springer Nature
References
- 1
Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).
- 2
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).
- 3
Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
- 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).
- 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).
- 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).
- 7
Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).
- 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).
- 9
Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016).
- 10
Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).
- 11
Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).
- 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).
- 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).
- 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).
- 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).
- 16
Lawson, L.J., Perry, V.H. & Gordon, S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48, 405–415 (1992).
- 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).
- 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).
- 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).
- 20
Salter, M.W. & Beggs, S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15–24 (2014).
- 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).
- 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).
- 23
Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).
- 24
Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).
- 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).
- 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).
- 27
Fontainhas, A.M. et al. Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLoS One 6, e15973 (2011).
- 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).
- 29
Dissing-Olesen, L. et al. Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth. J. Neurosci. 34, 10511–10527 (2014).
- 30
Tremblay, M.E., Lowery, R.L. & Majewska, A.K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).
- 31
Schafer, D.P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
- 32
Paolicelli, R.C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).
- 33
Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).
- 34
Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016).
- 35
van Lookeren Campagne, M., Wiesmann, C. & Brown, E.J. Macrophage complement receptors and pathogen clearance. Cell. Microbiol. 9, 2095–2102 (2007).
- 36
Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).
- 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).
- 38
Brown, G.C. & Neher, J.J. Microglial phagocytosis of live neurons. Nat. Rev. Neurosci. 15, 209–216 (2014).
- 39
Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016).
- 40
Marín-Teva, J.L. et al. Microglia promote the death of developing Purkinje cells. Neuron 41, 535–547 (2004).
- 41
Frade, J.M. & Barde, Y.A. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20, 35–41 (1998).
- 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).
- 43
Wakselman, S. et al. Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J. Neurosci. 28, 8138–8143 (2008).
- 44
Schafer, D.P. & Stevens, B. Microglia function in central nervous system development and plasticity. Cold Spring Harb. Perspect. Biol. 7, a020545 (2015).
- 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).
- 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).
- 47
Zhao, C., Deng, W. & Gage, F.H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008).
- 48
Akers, K.G. et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science 344, 598–602 (2014).
- 49
Rogers, J.T. et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J. Neurosci. 31, 16241–16250 (2011).
- 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).
- 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).
- 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).
- 53
Sipe, G.O. et al. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat. Commun. 7, 10905 (2016).
- 54
Sierra, A. et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483–495 (2010).
- 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).
- 56
Gemma, C. & Bachstetter, A.D. The role of microglia in adult hippocampal neurogenesis. Front. Cell. Neurosci. 7, 229 (2013).
- 57
Tremblay, M.E. et al. The role of microglia in the healthy brain. J. Neurosci. 31, 16064–16069 (2011).
- 58
Parkhurst, C.N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).
- 59
Butovsky, O. et al. Identification of a unique TGF-b-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).
- 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).
- 61
Murray, P.J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).
- 62
Ransohoff, R.M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).
- 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).
- 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).
- 65
Pardo, C.A., Vargas, D.L. & Zimmerman, A.W. Immunity, neuroglia and neuroinflammation in autism. Int. Rev. Psychiatry 17, 485–495 (2005).
- 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).
- 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).
- 68
Tetreault, N.A. et al. Microglia in the cerebral cortex in autism. J. Autism Dev. Disord. 42, 2569–2584 (2012).
- 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).
- 70
Suzuki, K. et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70, 49–58 (2013).
- 71
Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).
- 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).
- 73
Derecki, N.C. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (2012).
- 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).
- 75
Estes, M.L. & McAllister, A.K. Maternal immune activation: Implications for neuropsychiatric disorders. Science 353, 772–777 (2016).
- 76
Giovanoli, S. et al. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science 339, 1095–1099 (2013).
- 77
Patterson, P.H. Maternal infection and immune involvement in autism. Trends Mol. Med. 17, 389–394 (2011).
- 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).
- 79
Squarzoni, P. et al. Microglia modulate wiring of the embryonic forebrain. Cell Reports 8, 1271–1279 (2014).
- 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).
- 81
Feinberg, I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J. Psychiatr. Res. 17, 319–334 (1982–83).
- 82
Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).
- 83
Chen, S.K. et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775–785 (2010).
- 84
Paloneva, J. et al. CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts. Neurology 56, 1552–1558 (2001).
- 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).
- 86
McCarthy, M.M. Multifaceted origins of sex differences in the brain. Phil. Trans. R. Soc. Lond. B 371, 20150106 (2016).
- 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).
- 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).
- 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).
- 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).
- 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).
- 92
Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707–720 (2013).
- 93
Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).
- 94
Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).
- 95
Efthymiou, A.G. & Goate, A.M. Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener. 12, 43 (2017).
- 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).
- 97
Colonna, M. & Wang, Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 17, 201–207 (2016).
- 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).
- 99
Colonna, M. TREMs in the immune system and beyond. Nat. Rev. Immunol. 3, 445–453 (2003).
- 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).
- 101
Ulrich, J.D. et al. Altered microglial response to Ab plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014).
- 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).
- 103
Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015).
- 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).
- 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).
- 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).
- 107
Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med. 6, 243ra86 (2014).
- 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).
- 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).
- 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).
- 111
Griciuc, A. et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013).
- 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).
- 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).
- 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).
- 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).
- 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).
- 117
Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).
- 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).
- 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).
- 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).
- 121
Vasek, M.J. et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016).
- 122
Zamanian, J.L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).
- 123
Sofroniew, M.V. & Vinters, H.V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).
- 124
Clarke, L.E. & Barres, B.A. Emerging roles of astrocytes in neural circuit development. Nat. Rev. Neurosci. 14, 311–321 (2013).
- 125
Chung, W.S., Allen, N.J. & Eroglu, C. Astrocytes control synapse formation, function, and elimination. Cold Spring Harb. Perspect. Biol. 7, a020370 (2015).
- 126
Liddelow, S.A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
- 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).
- 128
Iaccarino, H.F. et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235 (2016).
- 129
Beggs, S., Trang, T. & Salter, M.W. P2X4R+ microglia drive neuropathic pain. Nat. Neurosci. 15, 1068–1073 (2012).
- 130
Sorge, R.E. et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat. Med. 18, 595–599 (2012).
- 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).
- 132
North, R.A. P2X receptors. Phil. Trans. R. Soc. Lond. B 371, 20150427 (2016).
- 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).
- 134
Burnstock, G. Purinergic mechanisms and pain. Adv. Pharmacol. 75, 91–137 (2016).
- 135
Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016).
- 136
Masuda, T. et al. Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. Nat. Commun. 5, 3771 (2014).
- 137
Masuda, T. et al. IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Reports 1, 334–340 (2012).
- 138
Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003).
- 139
Sorge, R.E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015).
- 140
Ferrini, F. et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis. Nat. Neurosci. 16, 183–192 (2013).
- 141
Macosko, E.Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015).
- 142
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169, 1276–1290.e17 (2017).
- 143
Pandya, H. et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat. Neurosci. 20, 753–759 (2017).
- 144
Muffat, J. et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat. Med. 22, 1358–1367 (2016).
- 145
Hammond, T.R. & Stevens, B. Increasing the neurological-disease toolbox using iPSC-derived microglia. Nat. Med. 22, 1206–1207 (2016).
- 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).
- 147
Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).
- 148
Choi, S.H. et al. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature 515, 274–278 (2014).
- 149
Abud, E.M. et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94, 278–293.e9 (2017).
- 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).
- 151
Coull, J.A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).
- 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).
- 153
Hodgkin, J. Sex determination and the generation of sexually dimorphic nervous systems. Neuron 6, 177–185 (1991).
- 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).
- 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).
- 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).
- 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).
- 158
McCullough, L.D. et al. Stroke sensitivity in the aged: sex chromosome complement vs. gonadal hormones. Aging (Albany. NY) 8, 1432–1441 (2016).
- 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).
- 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).
- 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).
- 162
Stellwagen, D. & Malenka, R.C. Synaptic scaling mediated by glial TNF-a. Nature 440, 1054–1059 (2006).
- 163
Shi, Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl. Med. 9, eaaf6295 (2017).
- 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).
- 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).
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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