Skip to main content
SpringerLink
Log in

Changes in the Microglial Population during Spinal Cord Formation Indicate an Involvement of Microglia in the Regulation of Neuronogenesis and Synaptogenesis

  • MECHANISMS OF NORMAL AND PATHOLOGICAL DEVELOPMENT
  • Published:
Russian Journal of Developmental Biology Aims and scope Submit manuscript

Abstract

The localization and distribution of microgliocytes in the spinal cord (SC) of rat embryos during the formation of motor neuron precursors were studied. Antibodies to the Iba1 protein were used for the identification of microglial cells. To study the dynamics of the development of embryonic SC cells, we used the following immunohistochemical markers: vimentin (a marker of radial glia cells), doublecortin (a marker of neuroblasts), and synaptophysin (a marker of synaptic vesicles). It is shown that microglia progenitors penetrate the dorsal part of the spinal cord on day 12 of embryonic development; they are detected in the area of emerging motor neurons on day 14. It was found that embryonic microgliocytes are in close relationship with the processes of the radial glia and the processes of the neuroblasts of the anterior horns. The study into the dynamics of the development of the rat embryonic SC and the comparison of the processes of its histogenesis with the localization and morphological changes of the embryonic microglia indicates its participation in synaptogenesis and the differentiation of motor neurons (neuronogenesis).

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others

REFERENCES

  1. Altman, J. and Bayer, S.A., Development of the Human Spinal Cord: An Interpretation Based on Experimental Studies in Animals, New York: Oxford University Press, 2001.

  2. Béchade, C., Pascual, O., Triller, A., and Bessis, A., Nitricoxide regulates astrocyte maturation in the hippocampus: involvement of NOS2, Mol. Cell. Neurosci., 2011, vol. 46, pp. 762–769.

    Article  PubMed  CAS  Google Scholar 

  3. Bennett, M.L., Bennett, F.C., Liddelow, S.A., et al., New tools for studying microglia in the mouse and human CNS, Proc. Natl. Acad. Sci. U. S. A., 2016, vol. 113, no. 12, pp. E1738–E1746.

  4. Calderó, J., Brunet, N., Ciutat, D., et al., Development of microglia in the chick embryo spinal cord: implications in the regulation of motoneuronal survival and death, J. Neurosci. Res., 2009, vol. 87, no. 11, pp. 2447–2466.

    Article  PubMed  CAS  Google Scholar 

  5. Chaboub, L.S. and Deneen, B., Developmental origins of astrocyte heterogeneity: the final frontier of CNS development, Dev. Neurosci., 2012, vol. 34, pp. 379–388.

    Article  CAS  PubMed  Google Scholar 

  6. Chamak, B., Morandi, V., and Mallat, M., Brain macrophages stimulate neurite growth and regeneration by secreting thrombospondin, J. Neurosci. Res., 1994, vol. 38, no. 2, pp. 221–233.

    Article  CAS  PubMed  Google Scholar 

  7. Chen, V.S., Morrison, J.P., Southwell, M.F., et al., Histology atlas of the developing prenatal and postnatal mouse central nervous system, with emphasis on prenatal days E7.5 to E18.5, Toxicol. Pathol., 2017, vol. 45, pp. 705–744.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Filipello, F., Morini, R., Corradini, I., et al., The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity, Immunity, 2018, vol. 48, no. 5.

  9. Ginhoux, F., Greter, M., Leboeuf, M., et al., Fate mapping analysis reveals that adult microglia derive from primitive macrophages, Science, 2010, vol. 330, no. 6005, pp. 841–845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hata, K., Fujitani, M., Yasuda, Y., et al., RGMa inhibition promotes axonal growth and recovery after spinal cord injury, J. Cell Biol., 2006, vol. 173, no. 1, pp. 47–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hua, J.Y. and Smith, S.J., Neural activity and the dynamics of central nervous system development, Nat. Neurosci., 2004, vol. 7, no. 4, pp. 327–332.

    Article  CAS  PubMed  Google Scholar 

  12. Kim, H.-J., Cho, M.-H., Shim, W.H., et al., Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects, Mol. Psychiatry, 2017, vol. 22, pp. 1576–1584.

    Article  CAS  PubMed  Google Scholar 

  13. Kolos, E.A. and Korzhevskii, D.E., Spinal cord microglia in health and disease, Acta Naturae, 2020, vol. 12, no. 1 (44), pp. 4–17.

  14. Kolos, E.A., Grigor’ev, I.P., and Korzhevskii, D.E., Synaptic contact marker synaptophysin, Morfologiya, 2015, vol. 147, no. 1, pp. 78–82.

    Google Scholar 

  15. Kongsui, R., Beynon, S.B., Johnson, S.J., and Walker, F.R., Quantitative assessment of microglial morphology and density reveals remarkable consistency in the distribution and morphology of cells within the healthy prefrontal cortex of the rat, J. Neuroinflam., 2014, no. 11, p. 182.

  16. Korzhevskii, D.E., Kirik, O.V., Sukhorukova, E.G., et al., Structural organization of striatal microgliocytes after transient focal ischemia, Morfologiya, 2012, vol. 141, no. 2, pp. 28–32.

    CAS  Google Scholar 

  17. Korzhevskii, D.E., Sukhorukova, E.G., Kirik, O.V., and Grigorev, I.P., Immunohistochemical demonstration of specific antigens in the human brain fixed in zinc-ethanol-formaldehyde, Eur. J. Histochem., 2015, vol. 59, no. 3, pp. 233–237.

  18. Kwon, S.E. and Chapman, E.R., Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons, Neuron, 2011, vol. 70, no. 5, pp. 47–54.

    Article  CAS  Google Scholar 

  19. Lenz, K.M. and Nelson, L.H., Microglia and beyond: innate immune cells as regulators of brain development and behavioral function, Front. Immunol., 2018, vol. 9, p. 698.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Li, Y., He, X., Kawaguchi, R., et al., Microglia-organized scar-free spinal cord repair in neonatal mice, Nature, 2020, vol. 587, no. 7835, pp. 613–618.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Marsters, C.M., Nesan, D., Far, R., et al., Embryonic microglia influence developing hypothalamic glial populations, J. Neuroinflam., 2020, vol. 17, p. 146.

    Article  CAS  Google Scholar 

  22. May, M.K. and Biscoe, T.J., An investigation of the foetal rat spinal cord i. ultrastructural observations on the onset of synaptogenesis, Cell Tissue Res., 1975, vol. 158, pp. 241–249.

    Article  CAS  PubMed  Google Scholar 

  23. Michell-Robinson, M.A., Touil, H., Healy, L.M., et al., Roles of microglia in brain development, tissue maintenance and repair, Brain, 2015, vol. 138, pp. 1138–1159.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Mosser, C.A., Baptista, S., Arnoux, I., and Audinat, E., Microglia in CNS development: shaping the brain for the future, Prog. Neurobiol., 2017, vols. 149–150, pp. 1–20.

    Article  PubMed  Google Scholar 

  25. Nagata, K., Nakajima, K., Takemoto, N., et al., Microglia-derived plasminogen enhances neurite outgrowth from explant cultures of rat brain, Int. J. Dev. Neurosci., 1993, vol. 11, pp. 227–237.

    Article  CAS  PubMed  Google Scholar 

  26. Pont-Lezica, L., Béchade, C., Belarif-Cantaut, Y., et al., Physiological roles of microglia during development, J. Neurochem., 2011, vol. 119, no. 5, pp. 901–908.

    Article  CAS  PubMed  Google Scholar 

  27. Pont-Lezica, L., Béchade, W., Colasse, S., et al., Microglia shape corpus callosum axon tract fasciculation: functional impact of prenatal inflammation, Eur. J. Neurosci., 2014, vol. 39, no. 10, pp. 1551–1557.

    Article  PubMed  Google Scholar 

  28. Prasad, T., Wang, X., Gray, P.A., and Weiner, J.A., A differential developmental pattern of spinal interneuron apoptosis during synaptogenesis: insights from genetic analyses of the protocadherin-γ gene cluster, Development, 2008, vol. 135, no. 24, pp. 4153–4164.

    Article  CAS  PubMed  Google Scholar 

  29. Reemst, K., Noctor, S.C., Lucassen, P.J., and Hol, E.M., The indispensable roles of microglia and astrocytes during brain development, Front. Hum. Neurosci., 2016, vol. 10, p. 566.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Rezaie, P. and Male, D., Colonisation of the developing human brain and spinal cord by microglia: a review, Microsc. Res. Tech., 1999, vol. 45, pp. 359–382.

    Article  CAS  PubMed  Google Scholar 

  31. Rigato, C., Buckinx, R., Le-Corronc, H., et al., Pattern of invasion of the embryonic mouse spinal cord by microglial cells at the time of the onset of functional neuronal networks, Glia, 2011, vol. 59, no. 4, pp. 675–695.

    Article  CAS  PubMed  Google Scholar 

  32. Sanchez-Lopez, A., Cuadros, M.A., Calvente, R., et al., Radial migration of developing microglial cells in quail retina: a confocal microscopy study, Glia, 2004, vol. 46, no. 3, pp. 261–273.

    Article  PubMed  Google Scholar 

  33. Schafer, D.P., Lehrman, E.K., Kautzman, A.G., et al., Microglia sculpt postnatal neural circuits in an activity- and complement-dependent manner, Neuron, 2012, vol. 74, pp. 691–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stence, N., Waite, M., and Dailey, M.E., Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices, Glia, 2001, vol. 33, no. 3, pp. 256–266.

    Article  CAS  PubMed  Google Scholar 

  35. Streit, W.J., Xue, Q.S., Tischer, J., and Bechmann, I., Microglial pathology, Acta Neuropathol. Commun., 2014, vol. 26, no. 2, p. 142.

    Article  Google Scholar 

  36. Sufieva, D.A., Razenkova, V.A., Antipova, M.V., and Korzhevskii, D.E., Microglia and tanycytes of the infundibular recess of the brain in early postnatal development and during aging, Russ. J. Dev. Biol., 2020, vol. 51, pp. 189–196.

    Article  Google Scholar 

  37. Swinnen, N., Smolders, S., Avila, A., et al., Complex invasion pattern of the cerebral cortex by microglial cells during development of the mouse embryo, Glia, 2013, vol. 61, no. 2, pp. 150–163.

    Article  PubMed  Google Scholar 

  38. Tay, T.L., Savage, J.C., Hui, C.W., et al., Microglia across the lifespan: from origin to function in brain development, plasticity and cognition, J. Physiol., 2017, vol. 595, no. 6, pp. 1929–1945.

    Article  CAS  PubMed  Google Scholar 

  39. Tien, A.C., Tsai, H.H., Molofsky, A.V., et al., Regulated temporal-spatial astrocyte precursor cell proliferation involves BRAF signalling in mammalian spinal cord, Development, 2012, vol. 139, pp. 2477–2487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tremblay, M.E., Lowery, R.L., and Majewska, A.K., Microglial interactions with synapses are modulated by visual experience, PLoS Biol., 2010, vol. 8. e1000527.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Tseng, C.Y., Ling, E.A., and Wong, W.C., Light and electron microscopic and cytochemical identification of amoeboid microglial cells in the brain of prenatal rats, J. Anat., 1983, vol. 136, pp. 837–849.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ueno, M., Fujita, Y., Tanaka, T., et al., Layer v cortical neurons require microglial support for survival during postnatal development, Nat. Neurosci., 2013, vol. 16, no. 5, pp. 543–551.

    Article  CAS  PubMed  Google Scholar 

  43. Vaughan, J.E. and Grieshaber, J.A., A morphological investigation of an early reflex pathway in developing rat spinal cord, J. Comp. Neurol., 1973, vol. 148, no. 2, pp. 177–209.

    Article  Google Scholar 

  44. Wake, H., Moorhouse, A.J., Jinno, S., et al., Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals, J. Neurosci., 2009, vol. 29, no. 13, pp. 3974–3980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, C.C., Wu, C.H., Shieh, J.Y., et al., Immunohistochemical study of amoeboid microglial cells in fetal rat brain, J. Anat., 1996, vol. 189, pp. 567–574.

    PubMed  PubMed Central  Google Scholar 

  46. Wehrle, R., Camand, E., Chedotal, A., et al., Expression of netrin-1, slit-1 and slit-3 but not of slit-2 after cerebellar and spinal cord lesions, Eur. J. Neurosci., 2005, vol. 22, pp. 2134–2144.

    Article  PubMed  Google Scholar 

  47. Yang, H., Feng, G.D., Liang, Z., et al., In vitro beneficial activation of microglial cells by mechanically-injured astrocytes enhances the synthesis and secretion of BDNF through p38MAPK, Neurochem. Int., 2012, vol. 61, no. 2, pp. 175–186.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The work was performed within the framework of State Assignment of Federal State Budgetary Scientific Institution “Institute of Experimental Medicine.”

Author information

Authors and Affiliations

  1. Institute of Experimental Medicine, 197367, St. Petersburg, Russia

    E. A. Kolos & D. E. Korzhevskii

Authors
  1. E. A. Kolos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. E. Korzhevskii
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors of this paper, E.A. Kolos and D.E. Korzhevskii, developed the experimental design, analyzed the material, participated in data processing, discussed the results, and wrote the text of the article.

Corresponding author

Correspondence to E. A. Kolos.

Ethics declarations

Conflict of interest. The authors declare that they have no conflict of interests.

Statement on the welfare of animals. In the course of this study, all manipulations with laboratory animals were carried out in accordance with the “Rules for Work with Experimental Animals” and in compliance with the European Convention for the Protection of Vertebrates Used for Experiments or for Other Scientific Purposes (1986). The study was approved by the Ethics Committee of the Federal State Budgetary Scientific Institution Institute of Experimental Medicine (Protocol no. 3/19, April 25, 2019).

Additional information

Translated by A. Ermakov

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kolos, E.A., Korzhevskii, D.E. Changes in the Microglial Population during Spinal Cord Formation Indicate an Involvement of Microglia in the Regulation of Neuronogenesis and Synaptogenesis. Russ J Dev Biol 52, 176–186 (2021). https://doi.org/10.1134/S1062360421030048

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1062360421030048

Keywords:

Search

Navigation