Brain Structure and Function

, Volume 222, Issue 6, pp 2759–2771 | Cite as

Microglia in the primate macula: specializations in microglial distribution and morphology with retinal position and with aging

  • Janani Singaravelu
  • Lian Zhao
  • Robert N. Fariss
  • T. Michael Nork
  • Wai T. WongEmail author
Original Article


Microglia, the principal resident immune cell in the retina, play constitutive roles in immune surveillance and synapse maintenance, and are also associated with retinal disease, including those occurring in the macula. Perspectives on retinal microglia function have derived largely from rodent models and how these relate to the macula-bearing primate retina is unclear. In this study, we examined microglial distribution and cellular morphology in the adult rhesus macaque retina, and performed comparative characterizations in three retinal locations along the center-to-periphery axis (parafoveal, macular, and the peripheral retina). We found that microglia density peaked in the parafoveal retina and decreased in the peripheral retina. Individual microglial morphology reflected macular specialization, with macular microglia demonstrating the largest and most complex dendritic arbors relative to other retinal locations. Comparing retinal microglia between young and middle-aged animals, microglial density increased in the macular, but not in the peripheral retina with age, while microglial morphology across all locations remained relatively unchanged. Our findings indicate that microglial distribution and morphology demonstrate regional specialization in the retina, correlating with gradients of other retinal cell types. As microglia are innate immune cells implicated in age-related macular diseases, age-related microglial changes may be related to the increased vulnerability of the aged macula to immune-related neurodegeneration.


Microglia Retina Macula Aging Primate Cellular morphology 



The authors are grateful to Dr. Peter MacLeish, Morehouse School of Medicine, Atlanta, GA, for the generous gift of the 7G6 antibody and to Dr. Paul Kaufman, Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, for his guidance and encouragement. This work is supported by the National Eye Institute Intramural Research Program. J.S. is supported by the NIH Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. T.M.N. is supported by NIH NEI Core Grant P30 EY016665, Research to Prevent Blindness, the Wisconsin National Primate Research Center P51RR000167/P51OD011106, and the Retina Research Foundation Catherine and Latimer Murfee chair.

Author contributions

JS, LZ, RNF, and WTW planned the experiments, JS and LZ conducted the experiments, TMN prepared materials for the experiments, JS and WTW wrote the manuscript. All authors reviewed the manuscript and provided critical comment.

Compliance with ethical standards

Conflict of interest

None of the authors have no conflicts of interest, financial, or personal, to disclose.

Supplementary material

429_2017_1370_MOESM1_ESM.pdf (692 kb)
Supplementary material 1 (PDF 691 KB)


  1. Barkholt P, Sanchez-Guajardo V, Kirik D, Romero-Ramos M (2012) Long-term polarization of microglia upon alpha-synuclein overexpression in nonhuman primates. Neuroscience 208:85–96. doi: 10.1016/j.neuroscience.2012.02.004 CrossRefPubMedGoogle Scholar
  2. Boycott BB, Hopkins JM (1981) Microglia in the retina of monkey and other mammals: its distinction from other types of glia and horizontal cells. Neuroscience 6(4):679–688CrossRefPubMedGoogle Scholar
  3. Chen M, Xu H (2015) Parainflammation, chronic inflammation, and age-related macular degeneration. J Leukoc Biol 98(5):713–725. doi: 10.1189/jlb.3RI0615-239R CrossRefPubMedPubMedCentralGoogle Scholar
  4. Curcio CA (2001) Photoreceptor topography in ageing and age-related maculopathy. Eye 15(Pt 3):376–383. doi: 10.1038/eye.2001.140 Google Scholar
  5. Curcio CA, Sloan KR Jr, Packer O, Hendrickson AE, Kalina RE (1987) Distribution of cones in human and monkey retina: individual variability and radial asymmetry. Science 236(4801):579–582CrossRefPubMedGoogle Scholar
  6. Damani MR, Zhao L, Fontainhas AM, Amaral J, Fariss RN, Wong WT (2011) Age-related alterations in the dynamic behavior of microglia. Aging cell 10(2):263–276. doi: 10.1111/j.1474-9726.2010.00660.x CrossRefPubMedGoogle Scholar
  7. Diaz-Araya CM, Provis JM, Penfold PL, Billson FA (1995) Development of microglial topography in human retina. J Comp Neurol 363(1):53–68. doi: 10.1002/cne.903630106 CrossRefPubMedGoogle Scholar
  8. Eyo UB, Wu LJ (2013) Bidirectional microglia-neuron communication in the healthy brain. Neural Plast 2013:456857. doi: 10.1155/2013/456857 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Fontainhas AM, Wang M, Liang KJ, Chen S, Mettu P, Damani M, Fariss RN, Li W, Wong WT (2011) Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PloS one 6(1):e15973. doi: 10.1371/journal.pone.0015973 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Frost JL, Schafer DP (2016) Microglia: architects of the developing nervous system. Trends Cell Biol. doi: 10.1016/j.tcb.2016.02.006 PubMedPubMedCentralGoogle Scholar
  11. Gomez-Nicola D, Perry VH (2015) Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neuroscientist 21(2):169–184. doi: 10.1177/1073858414530512 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Hefendehl JK, Neher JJ, Suhs RB, Kohsaka S, Skodras A, Jucker M (2014) Homeostatic and injury-induced microglia behavior in the aging brain. Aging cell 13(1):60–69. doi: 10.1111/acel.12149 CrossRefPubMedGoogle Scholar
  13. Hendrickson AE, Yuodelis C (1984) The morphological development of the human fovea. Ophthalmology 91(6):603–612CrossRefPubMedGoogle Scholar
  14. Hristovska I, Pascual O (2015) Deciphering resting microglial morphology and process motility from a synaptic prospect. Front Integr Neurosci 9:73. doi: 10.3389/fnint.2015.00073 PubMedGoogle Scholar
  15. Karlstetter M, Langmann T (2014) Microglia in the aging retina. Adv Exp Med Biol 801:207–212. doi: 10.1007/978-1-4614-3209-8_27 CrossRefPubMedGoogle Scholar
  16. Karlstetter M, Scholz R, Rutar M, Wong WT, Provis JM, Langmann T (2015) Retinal microglia: just bystander or target for therapy? Prog Retin Eye Res 45:30–57. doi: 10.1016/j.preteyeres.2014.11.004 CrossRefPubMedGoogle Scholar
  17. Lee JE, Liang KJ, Fariss RN, Wong WT (2008) Ex vivo dynamic imaging of retinal microglia using time-lapse confocal microscopy. Investig Ophthalmol Visual Sci 49(9):4169–4176. doi: 10.1167/iovs.08-2076 CrossRefGoogle Scholar
  18. Li Y, Du XF, Liu CS, Wen ZL, Du JL (2012) Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell 23(6):1189–1202. doi: 10.1016/j.devcel.2012.10.027 CrossRefPubMedGoogle Scholar
  19. Li L, Eter N, Heiduschka P (2015) The microglia in healthy and diseased retina. Exp Eye Res 136:116–130. doi: 10.1016/j.exer.2015.04.020 CrossRefPubMedGoogle Scholar
  20. Ma W, Wong WT (2016) Aging changes in retinal microglia and their relevance to age-related retinal disease. Adv Exp Med Biol 854:73–78. doi: 10.1007/978-3-319-17121-0_11 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Ma W, Cojocaru R, Gotoh N, Gieser L, Villasmil R, Cogliati T, Swaroop A, Wong WT (2013) Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation. Neurobiol Aging 34(10):2310–2321. doi: 10.1016/j.neurobiolaging.2013.03.022 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Madeira MH, Boia R, Santos PF, Ambrosio AF, Santiago AR (2015) Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases. Mediators Inflamm 2015:673090. doi: 10.1155/2015/673090 CrossRefPubMedPubMedCentralGoogle Scholar
  23. McGeer PL, McGeer EG (2015) Targeting microglia for the treatment of Alzheimer’s disease. Expert Opin Ther Targets 19(4):497–506. doi: 10.1517/14728222.2014.988707 CrossRefPubMedGoogle Scholar
  24. Ng TF, Streilein JW (2001) Light-induced migration of retinal microglia into the subretinal space. Invest Ophthalmol Visual Sci 42 (13):3301–3310Google Scholar
  25. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. doi: 10.1126/science.1110647 CrossRefPubMedGoogle Scholar
  26. Norden DM, Muccigrosso MM, Godbout JP (2015) Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology 96(Pt A):29–41. doi: 10.1016/j.neuropharm.2014.10.028 Google Scholar
  27. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, Hempstead BL, Littman DR, Gan WB (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155(7):1596–1609. doi: 10.1016/j.cell.2013.11.030 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Penfold PL, Madigan MC, Provis JM (1991) Antibodies to human leucocyte antigens indicate subpopulations of microglia in human retina. Vis Neurosci 7(4):383–388CrossRefPubMedGoogle Scholar
  29. Penfold PL, Provis JM, Liew SC (1993) Human retinal microglia express phenotypic characteristics in common with dendritic antigen-presenting cells. J Neuroimmunol 45(1–2):183–191CrossRefPubMedGoogle Scholar
  30. Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10(4):217–224. doi: 10.1038/nrneurol.2014.38 CrossRefPubMedGoogle Scholar
  31. Provis JM, Penfold PL, Edwards AJ, van Driel D (1995) Human retinal microglia: expression of immune markers and relationship to the glia limitans. Glia 14(4):243–256. doi: 10.1002/glia.440140402 CrossRefPubMedGoogle Scholar
  32. Schmidt AF, Kannan PS, Chougnet CA, Danzer SC, Miller LA, Jobe AH, Kallapur SG (2016) Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques. J Neuroinflammation 13(1):238. doi: 10.1186/s12974-016-0706-4 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Tay TL, Savage J, Hui CW, Bisht K, Tremblay ME (2016) Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J Physiol. doi: 10.1113/JP272134 PubMedGoogle Scholar
  34. Thanos S (1992) Sick photoreceptors attract activated microglia from the ganglion cell layer: a model to study the inflammatory cascades in rats with inherited retinal dystrophy. Brain Res 588(1):21–28CrossRefPubMedGoogle Scholar
  35. Tonchev AB, Yamashima T, Zhao L, Okano H (2003) Differential proliferative response in the postischemic hippocampus, temporal cortex, and olfactory bulb of young adult macaque monkeys. Glia 42(3):209–224. doi: 10.1002/glia.10209 CrossRefPubMedGoogle Scholar
  36. Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8(11):e1000527. doi: 10.1371/journal.pbio.1000527 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Tremblay ME, Zettel ML, Ison JR, Allen PD, Majewska AK (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60(4):541–558. doi: 10.1002/glia.22287 CrossRefPubMedPubMedCentralGoogle Scholar
  38. von Bernhardi R, Eugenin-von Bernhardi L, Eugenin J (2015) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 7:124. doi: 10.3389/fnagi.2015.00124 Google Scholar
  39. Vrabec F (1970) Microglia in the monkey and rabbit retina. J Neuropathol Exp Neurol 29(2):217–224CrossRefPubMedGoogle Scholar
  40. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29(13):3974–3980. doi: 10.1523/JNEUROSCI.4363-08.2009 CrossRefPubMedGoogle Scholar
  41. Walker FR, Beynon SB, Jones KA, Zhao Z, Kongsui R, Cairns M, Nilsson M (2014) Dynamic structural remodelling of microglia in health and disease: a review of the models, the signals and the mechanisms. Brain Behav Immun 37:1–14. doi: 10.1016/j.bbi.2013.12.010 CrossRefPubMedGoogle Scholar
  42. Wang M, Wang X, Zhao L, Ma W, Rodriguez IR, Fariss RN, Wong WT (2014) Macroglia-microglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J Neurosci 34(10):3793–3806. doi: 10.1523/JNEUROSCI.3153-13.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wang X, Zhao L, Zhang J, Fariss RN, Ma W, Kretschmer F, Wang M, Qian HH, Badea TC, Diamond JS, Gan WB, Roger JE, Wong WT (2016) Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina. J Neurosci 36(9):2827–2842. doi: 10.1523/JNEUROSCI.3575-15.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  44. West RW (1978) Bipolar and horizontal cells of the gray squirrel retina: Golgi morphology and receptor connections. Vision Res 18(2):129–136CrossRefPubMedGoogle Scholar
  45. Wikler KC, Rakic P, Bhattacharyya N, Macleish PR (1997) Early emergence of photoreceptor mosaicism in the primate retina revealed by a novel cone-specific monoclonal antibody. J Comp Neurol 377(4):500–508CrossRefPubMedGoogle Scholar
  46. Wong WT (2013) Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Front Cell Neurosci 7:22. doi: 10.3389/fncel.2013.00022 PubMedPubMedCentralGoogle Scholar
  47. Zhang H, Cuenca N, Ivanova T, Church-Kopish J, Frederick JM, MacLeish PR, Baehr W (2003) Identification and light-dependent translocation of a cone-specific antigen, cone arrestin, recognized by monoclonal antibody 7G6. Invest Ophthalmol Visual Sci 44(7):2858–2867CrossRefGoogle Scholar
  48. Zhao L, Zabel MK, Wang X, Ma W, Shah P, Fariss RN, Qian H, Parkhurst CN, Gan WB, Wong WT (2015) Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Mol Med 7(9):1179–1197. doi: 10.15252/emmm.201505298 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2017

Authors and Affiliations

  1. 1.Unit on Neuron-Glia Interactions in Retinal Disease, National Eye InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Biological Imaging Core, National Eye InstituteNational Institutes of HealthBethesdaUSA
  3. 3.Department of Ophthalmology and Visual SciencesUniversity of Wisconsin-MadisonMadisonUSA

Personalised recommendations