Skip to main content
SpringerLink
Log in

Morphology of Microglia Across Contexts of Health and Disease

  • Protocol
  • First Online:
Microglia

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2034))

Abstract

Microglia, the brain’s resident macrophages, are incredibly plastic and dynamic cells. In this chapter, we aim to describe and classify the many morphological changes they can display in normal development, aging, and disease. Although microglia in healthy adult brain tissue are often ramified with small somas, they can undergo massive and rapid morphological shifts in response to stimuli, becoming amoeboid or hypertrophic. Older animals occasionally contain dystrophic, senescent, and gitter cell-like microglia, and brain injury can be accompanied by an increase in rod cells. By a careful study of microglial morphology, coupled with ultrastructural insights gleaned using electron microscopy, insights can be provided into the functions performed by these various morphological phenotypes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Sierra A, de Castro F, Del Río-Hortega J et al (2016) 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. https://doi.org/10.1002/glia.23046

    Article  PubMed  Google Scholar 

  2. Jinno S, Fleischer F, Eckel S et al (2007) Spatial arrangement of microglia in the mouse hippocampus: a stereological study in comparison with astrocytes. Glia 55:1334–1347. https://doi.org/10.1002/(SICI)1096-9861(19970224)378:4<482::AID-CNE4>3.0.CO;2-Z

    Article  PubMed  Google Scholar 

  3. Boche D, Perry VH, Nicoll JAR (2013) Review: Activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39:3–18. https://doi.org/10.1111/j.1600-065X.2006.00441.x

    Article  CAS  PubMed  Google Scholar 

  4. Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000 Prime Rep. https://doi.org/10.12703/P6-13

  5. Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353:777–783. https://doi.org/10.1126/science.aag2590

    Article  CAS  PubMed  Google Scholar 

  6. del Rio-Hortega P (1932) Microglia. In: Penfield W (ed) Cytology and cellular pathology of the nervous system, vol 2. P.B. Hoeber, Inc, New York, pp 482–534

    Google Scholar 

  7. Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170

    Article  CAS  PubMed  Google Scholar 

  8. Tay TL, Savage JC, Hui C-W et al (2017) Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J Physiol Lond 595:1929–1945. https://doi.org/10.1113/JP272134

    Article  CAS  PubMed  Google Scholar 

  9. Davalos D, Grutzendler J, Yang G et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758. https://doi.org/10.1038/nn1472

    Article  CAS  PubMed  Google Scholar 

  10. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. https://doi.org/10.1126/science.1110647

    Article  CAS  PubMed  Google Scholar 

  11. Tremblay M-È, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527. https://doi.org/10.1371/journal.pbio.1000527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tremblay M-È, Zettel ML, Ison JR et al (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60:541–558. https://doi.org/10.1002/glia.22287

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bisht K, Sharma KP, Lecours C et al (2016) Dark microglia: a new phenotype predominantly associated with pathological states. Glia. https://doi.org/10.1002/glia.22966

    Article  PubMed  PubMed Central  Google Scholar 

  14. Vinet J, Weering HRJV, Heinrich A et al (2012) Neuroprotective function for ramified microglia in hippocampal excitotoxicity. J Neuroinflammation 9:27. https://doi.org/10.1186/1742-2094-9-27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sierra A, Encinas JM, Deudero JJP et al (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495. https://doi.org/10.1016/j.stem.2010.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Madry C, Kyrargyri V, Arancibia-Cárcamo IL et al (2017) Microglial ramification, surveillance, and interleukin-1b release are regulated by the two-pore domain K. Neuron 97(2):299–312.e6. https://doi.org/10.1016/j.neuron.2017.12.002

    Article  CAS  PubMed  Google Scholar 

  17. Fourgeaud L, Través PG, Tufail Y et al (2016) TAM receptors regulate multiple features of microglial physiology. Nature 532:240–244. https://doi.org/10.1038/nature17630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tremblay M-È, Marker DF, Puccini JM et al (2013) Ultrastructure of microglia-synapse interactions in the HIV-1 Tat-injected murine central nervous system. Commun Integr Biol 6:e27670. https://doi.org/10.4161/cib.27670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hagemeyer N, Hanft K-M, Akriditou M-A et al (2017) Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol 134:441–458. https://doi.org/10.1002/glia.20469

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bennett ML, Bennett FC, Liddelow SA et al (2016) New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci U S A 113:E1738–E1746. https://doi.org/10.1186/1471-2105-15-293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Perez-Pouchoulen M, VanRyzin JW, McCarthy MM (2015) Morphological and phagocytic profile of microglia in the developing rat cerebellum. eNeuro. https://doi.org/10.1523/ENEURO.0036-15.2015

    Article  PubMed  PubMed Central  Google Scholar 

  22. Parakalan R, Jiang B, Nimmi B et al (2012) Transcriptome analysis of amoeboid and ramified microglia isolated from the corpus callosum of rat brain. BMC Neurosci 13:64. https://doi.org/10.1186/1471-2202-13-64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bouvier DS, Jones EV, Quesseveur G et al (2016) High resolution dissection of reactive glial nets in Alzheimer’s disease. Sci Rep 6:24544. https://doi.org/10.1038/srep24544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bachstetter AD, Van Eldik LJ, Schmitt FA et al (2015) Disease-related microglia heterogeneity in the hippocampus of Alzheimer’s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun 3:32. https://doi.org/10.1186/s40478-015-0209-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shobin E, Bowley MP, Estrada LI et al (2017) Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey. GeroScience 39:199–220. https://doi.org/10.1016/j.neurobiolaging.2007.03.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Barger N, Keiter J, Kreutz A et al (2018) Microglia: an intrinsic component of the proliferative zones in the fetal rhesus monkey (Macaca mulatta) cerebral cortex. Cereb Cortex 117:145. https://doi.org/10.1093/cercor/bhy145

    Article  Google Scholar 

  27. Maxan A, Mason S, Saint-Pierre M et al (2018) Outcome of cell suspension allografts in a patient with Huntington’s disease. Ann Neurol 17:41. https://doi.org/10.1007/s00401-016-1582-9

    Article  CAS  Google Scholar 

  28. Zanier ER, Fumagalli S, Perego C et al (2015) Shape descriptors of the “never resting” microglia in three different acute brain injury models in mice. Intensive Care Med Exp 3:39. https://doi.org/10.1186/s40635-015-0039-0

    Article  PubMed  Google Scholar 

  29. Walker DG, Lue L-F (2015) Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther 7(1):56. https://doi.org/10.1186/s13195-015-0139-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Streit WJ, Sparks DL (1997) Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med 75:130–138

    Article  CAS  PubMed  Google Scholar 

  31. Raj DDA, Jaarsma D, Holtman IR et al (2014) Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol Aging 35:2147–2160. https://doi.org/10.1016/j.neurobiolaging.2014.03.025

    Article  CAS  PubMed  Google Scholar 

  32. Hellwig S, Brioschi S, Dieni S et al (2016) Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient mice. Brain Behav Immun 55:126–137. https://doi.org/10.1016/j.bbi.2015.11.008

    Article  PubMed  Google Scholar 

  33. Hinwood M, Tynan RJ, Charnley JL et al (2013) Chronic stress induced remodeling of the prefrontal cortex: structural re-organization of microglia and the inhibitory effect of minocycline. Cereb Cortex 23:1784–1797. https://doi.org/10.1093/cercor/bhs151

    Article  PubMed  Google Scholar 

  34. Hui C-W, St-Pierre M-K, Detuncq J et al (2018) Nonfunctional mutant Wrn protein leads to neurological deficits, neuronal stress, microglial alteration, and immune imbalance in a mouse model of Werner syndrome. Brain Behav Immun 73:450–469. https://doi.org/10.1016/j.bbi.2018.06.007

    Article  CAS  PubMed  Google Scholar 

  35. Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10:217–224. https://doi.org/10.1038/nrneurol.2014.38

    Article  CAS  PubMed  Google Scholar 

  36. Norden DM, Godbout JP (2013) Review: Microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39:19–34. https://doi.org/10.1016/j.bbi.2011.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Keren-Shaul H, Spinrad A, Weiner A et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169(7):1276–1290.e17. https://doi.org/10.1016/j.cell.2017.05.018

    Article  CAS  PubMed  Google Scholar 

  38. Griciuc A, Serrano-Pozo A, Parrado AR et al (2013) Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631–643. https://doi.org/10.1016/j.neuron.2013.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Graeber MB (2010) Changing face of microglia. Science 330:783–788. https://doi.org/10.1126/science.1190929

    Article  CAS  PubMed  Google Scholar 

  40. Tam WY, Ma CHE (2014) Bipolar/rod-shaped microglia are proliferating microglia with distinct M1/M2 phenotypes. Nat Publ Group 4:367. https://doi.org/10.1039/c3cc48934e

    Article  CAS  Google Scholar 

  41. Taylor SE, Morganti-Kossmann C, Lifshitz J, Ziebell JM (2014) Rod microglia: a morphological definition. PLoS One 9:e97096. https://doi.org/10.1371/journal.pone.0097096.t001

    Article  PubMed  PubMed Central  Google Scholar 

  42. Ziebell JM, Taylor SE, Cao T et al (2012) Rod microglia: elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury. J Neuroinflammation 9:247. https://doi.org/10.1186/1742-2094-9-247

    Article  PubMed  PubMed Central  Google Scholar 

  43. Jørgensen MB, Finsen BR, Jensen MB et al (1993) Microglial and astroglial reactions to ischemic and kainic acid-induced lesions of the adult rat hippocampus. Exp Neurol 120:70–88. https://doi.org/10.1006/exnr.1993.1041

    Article  PubMed  Google Scholar 

  44. Wirenfeldt M, Clare R, Tung S et al (2009) Increased activation of Iba1+ microglia in pediatric epilepsy patients with Rasmussen’s encephalitis compared with cortical dysplasia and tuberous sclerosis complex. Neurobiol Dis 34:432–440. https://doi.org/10.1016/j.nbd.2009.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lambertsen KL, Deierborg T, Gregersen R et al (2011) Differences in origin of reactive microglia in bone marrow chimeric mouse and rat after transient global ischemia. J Neuropathol Exp Neurol 70:481–494. https://doi.org/10.1097/NEN.0b013e31821db3aa

    Article  PubMed  Google Scholar 

  46. Bachstetter AD, Ighodaro ET, Hassoun Y et al (2017) Rod-shaped microglia morphology is associated with aging in 2 human autopsy series. Neurobiol Aging 52:98–105. https://doi.org/10.1016/j.neurobiolaging.2016.12.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Streit WJ, Xue Q-S, Tischer J, Bechmann I (2014) Microglial pathology. Acta Neuropathol Commun 2:142. https://doi.org/10.1186/s40478-014-0142-6

    Article  PubMed  PubMed Central  Google Scholar 

  48. Streit WJ, Braak H, Xue Q-S, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118:475–485. https://doi.org/10.1016/S0002-9440(10)65184-X

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tischer J, Krueger M, Mueller W et al (2016) Inhomogeneous distribution of Iba-1 characterizes microglial pathology in Alzheimer’s disease. Glia 64:1562–1572. https://doi.org/10.1002/glia.23024

    Article  PubMed  Google Scholar 

  50. Johnson EA, Dao TL, Guignet MA et al (2011) Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats. J Neuroinflammation 8:41. https://doi.org/10.1186/1742-2094-8-41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fendrick SE, Xue Q-S, Streit WJ (2007) Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene. J Neuroinflammation 4:9. https://doi.org/10.1186/1742-2094-4-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xue Q-S, Yang C, Hoffman PM, Streit WJ (2010) Microglial response to murine leukemia virus-induced encephalopathy is a good indicator of neuronal perturbations. Brain Res 1319:131–141. https://doi.org/10.1016/j.brainres.2009.12.089

    Article  CAS  PubMed  Google Scholar 

  53. Davies DS, Ma J, Jegathees T, Goldsbury C (2016) Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer’s disease. Brain Pathol 55:687. https://doi.org/10.1016/j.cell.2013.03.030

    Article  CAS  Google Scholar 

  54. Thériault P, Rivest S (2016) Microglia: senescence impairs clearance of myelin debris. Curr Biol 26:R772–R775. https://doi.org/10.1016/j.cub.2016.06.066

    Article  CAS  PubMed  Google Scholar 

  55. Safaiyan S, Kannaiyan N, Snaidero N et al (2016) Age-related myelin degradation burdens the clearance function of microglia during aging. Nat Neurosci 19:995–998. https://doi.org/10.1038/nn.4325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Baalman K, Marin MA, Ho TSY et al (2015) Axon initial segment-associated microglia. J Neurosci 35:2283–2292. https://doi.org/10.1523/JNEUROSCI.3751-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wogram E, Wendt S, Matyash M et al (2016) Satellite microglia show spontaneous electrical activity that is uncorrelated with activity of the attached neuron. Eur J Neurosci 43:1523–1534. https://doi.org/10.1152/jn.01210.2007

    Article  PubMed  Google Scholar 

  58. Trapp BD, Wujek JR, Criste GA et al (2007) Evidence for synaptic stripping by cortical microglia. Glia 55:360–368. https://doi.org/10.1002/glia.20462

    Article  PubMed  Google Scholar 

  59. Gorse KM, Lafrenaye AD (2018) The importance of inter-species variation in traumatic brain injury-induced alterations of microglial-axonal interactions. Front Neurol 9:778. https://doi.org/10.3389/fneur.2018.00778

    Article  PubMed  PubMed Central  Google Scholar 

  60. Savage JC, Picard K, González-Ibáñez F, Tremblay M-È (2018) A brief history of microglial ultrastructure: distinctive features, phenotypes, and functions discovered over the past 60 years by electron microscopy. Front Immunol 9:803. https://doi.org/10.3389/fimmu.2018.00803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Almolda B, González B, Castellano B (2013) Microglia detection by enzymatic histochemistry. In: Joseph B, Venero JL (eds) Microglia: methods and protocols. Humana, Totowa, NJ, pp 243–259

    Chapter  Google Scholar 

  62. Bolasco G, Weinhard L, Boissonnet T et al Three-dimensional nanostructure of an intact microglial cell. Front Neuroanat 12:105

    Google Scholar 

  63. Das GD (1976) Gitter cells and their relationship to macrophages in the developing cerebellum: an electron microscopic study. Virchows Arch B Cell Pathol 20:299–305

    CAS  PubMed  Google Scholar 

  64. Innocenti GM, Clarke S, Koppel H (1983) Transitory macrophages in the white matter of the developing visual cortex. II. Development and relations with axonal pathways. Brain Res 313:55–66

    Article  CAS  PubMed  Google Scholar 

  65. Butovsky O, Siddiqui S, Gabriely G et al (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122:3063–3087. https://doi.org/10.1172/JCI62636DS1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hui CW, St-Pierre A, Hajj El H et al (2018) Prenatal immune challenge in mice leads to partly sex-dependent behavioral, microglial, and molecular abnormalities associated with schizophrenia. Front Mol Neurosci 11:13. https://doi.org/10.3389/fnmol.2018.00013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Alboni S, Poggini S, Garofalo S et al (2016) Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment. Brain Behav Immun 58:261–271. https://doi.org/10.1016/j.bbi.2016.07.155

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada

    Julie C. Savage, Micaël Carrier & Marie-Ève Tremblay

  2. Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC, Canada

    Marie-Ève Tremblay

Authors
  1. Julie C. Savage
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Micaël Carrier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-Ève Tremblay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marie-Ève Tremblay .

Editor information

Editors and Affiliations

  1. Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, Tübingen, Germany

    Olga Garaschuk

  2. Faculty of Biology, Medicine and Health The University of Manchester, , Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen, Denmark, Achucarro Center for Neuroscience IKERBASQUE Basque Foundation for Science Bilbao, Spain, Manchester, UK

    Alexei Verkhratsky

Rights and permissions

Reprints and permissions

Copyright information

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

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Savage, J.C., Carrier, M., Tremblay, MÈ. (2019). Morphology of Microglia Across Contexts of Health and Disease. In: Garaschuk, O., Verkhratsky, A. (eds) Microglia. Methods in Molecular Biology, vol 2034. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9658-2_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9658-2_2

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9657-5

  • Online ISBN: 978-1-4939-9658-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation