Microglia Phagocytose Myelin Sheaths to Modify Developmental Myelination

Overview

Journal Nat Neurosci

Date 2020 Jul 8

PMID 32632287

Citations 155

Authors

Alexandria N Hughes

Bruce Appel

Affiliations

Soon will be listed here.

Abstract

During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similarly to neurons and synapses, excess myelin sheaths are produced and selectively eliminated, but how elimination occurs is unknown. Microglia, the resident immune cells of the central nervous system, engulf surplus neurons and synapses. To determine whether microglia also prune myelin sheaths, we used zebrafish to visualize and manipulate interactions between microglia, oligodendrocytes, and neurons during development. We found that microglia closely associate with oligodendrocytes and specifically phagocytose myelin sheaths. By using a combination of optical, genetic, chemogenetic, and behavioral approaches, we reveal that neuronal activity bidirectionally balances microglial association with neuronal cell bodies and myelin phagocytosis in the optic tectum. Furthermore, multiple strategies to deplete microglia resulted in oligodendrocytes maintaining excessive and ectopic myelin. Our work reveals a neuronal activity-regulated role for microglia in modifying developmental myelin targeting by oligodendrocytes.

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References

Uranova N, Vikhreva O, Rachmanova V, Orlovskaya D . Ultrastructural alterations of myelinated fibers and oligodendrocytes in the prefrontal cortex in schizophrenia: a postmortem morphometric study. Schizophr Res Treatment. 2012; 2011:325789. PMC: 3420756. DOI: 10.1155/2011/325789. View

Hines J, Ravanelli A, Schwindt R, Scott E, Appel B . Neuronal activity biases axon selection for myelination in vivo. Nat Neurosci. 2015; 18(5):683-9. PMC: 4414883. DOI: 10.1038/nn.3992. View

McKenzie I, Ohayon D, Li H, de Faria J, Emery B, Tohyama K . Motor skill learning requires active central myelination. Science. 2014; 346(6207):318-22. PMC: 6324726. DOI: 10.1126/science.1254960. View

Sampaio-Baptista C, Khrapitchev A, Foxley S, Schlagheck T, Scholz J, Jbabdi S . Motor skill learning induces changes in white matter microstructure and myelination. J Neurosci. 2013; 33(50):19499-503. PMC: 3858622. DOI: 10.1523/JNEUROSCI.3048-13.2013. View

Herbomel P, Thisse B, Thisse C . Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process. Dev Biol. 2002; 238(2):274-88. DOI: 10.1006/dbio.2001.0393. View

Nelson H, Treichel A, Eggum E, Martell M, Kaiser A, Trudel A . Individual neuronal subtypes control initial myelin sheath growth and stabilization. Neural Dev. 2020; 15(1):12. PMC: 7523326. DOI: 10.1186/s13064-020-00149-3. View

Liu P, Du J, He C . Developmental pruning of early-stage myelin segments during CNS myelination in vivo. Cell Res. 2013; 23(7):962-4. PMC: 3698634. DOI: 10.1038/cr.2013.62. View

Brown G, Neher J . Microglial phagocytosis of live neurons. Nat Rev Neurosci. 2014; 15(4):209-16. DOI: 10.1038/nrn3710. View

Neumann H, Kotter M, Franklin R . Debris clearance by microglia: an essential link between degeneration and regeneration. Brain. 2008; 132(Pt 2):288-95. PMC: 2640215. DOI: 10.1093/brain/awn109. View

10.

Almeida R, Lyons D . Oligodendrocyte Development in the Absence of Their Target Axons In Vivo. PLoS One. 2016; 11(10):e0164432. PMC: 5055324. DOI: 10.1371/journal.pone.0164432. View

11.

Green L, Nebiolo J, Smith C . Microglia exit the CNS in spinal root avulsion. PLoS Biol. 2019; 17(2):e3000159. PMC: 6402705. DOI: 10.1371/journal.pbio.3000159. View

12.

Li Q, Cheng Z, Zhou L, Darmanis S, Neff N, Okamoto J . Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing. Neuron. 2019; 101(2):207-223.e10. PMC: 6336504. DOI: 10.1016/j.neuron.2018.12.006. View

13.

Elazar N, Vainshtein A, Golan N, Vijayaragavan B, Schaeren-Wiemers N, Eshed-Eisenbach Y . Axoglial Adhesion by Cadm4 Regulates CNS Myelination. Neuron. 2018; 101(2):224-231.e5. PMC: 6371057. DOI: 10.1016/j.neuron.2018.11.032. View

14.

Nevin L, Robles E, Baier H, Scott E . Focusing on optic tectum circuitry through the lens of genetics. BMC Biol. 2010; 8:126. PMC: 2949621. DOI: 10.1186/1741-7007-8-126. View

15.

Wang Y, DelRosso N, Vaidyanathan T, Cahill M, Reitman M, Pittolo S . Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology. Nat Neurosci. 2019; 22(11):1936-1944. PMC: 6858541. DOI: 10.1038/s41593-019-0492-2. View

16.

van der Laan L, Ruuls S, Weber K, Lodder I, Dopp E, Dijkstra C . Macrophage phagocytosis of myelin in vitro determined by flow cytometry: phagocytosis is mediated by CR3 and induces production of tumor necrosis factor-alpha and nitric oxide. J Neuroimmunol. 1996; 70(2):145-52. DOI: 10.1016/s0165-5728(96)00110-5. View

17.

Mensch S, Baraban M, Almeida R, Czopka T, Ausborn J, El Manira A . Synaptic vesicle release regulates myelin sheath number of individual oligodendrocytes in vivo. Nat Neurosci. 2015; 18(5):628-30. PMC: 4427868. DOI: 10.1038/nn.3991. View

18.

Stowell R, Sipe G, Dawes R, Batchelor H, Lordy K, Whitelaw B . Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex. Nat Neurosci. 2019; 22(11):1782-1792. PMC: 6875777. DOI: 10.1038/s41593-019-0514-0. View

19.

Liu Y, Ying Y, Li Y, Eyo U, Chen T, Zheng J . Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling. Nat Neurosci. 2019; 22(11):1771-1781. PMC: 6858573. DOI: 10.1038/s41593-019-0511-3. View

20.

Eichhoff G, Brawek B, Garaschuk O . Microglial calcium signal acts as a rapid sensor of single neuron damage in vivo. Biochim Biophys Acta. 2010; 1813(5):1014-24. DOI: 10.1016/j.bbamcr.2010.10.018. View