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Vesicular release of glutamate from unmyelinated axons in white matter

Nature Neuroscience volume 10, pages 321–330 (2007)Cite this article

Abstract

Directed fusion of transmitter-laden vesicles enables rapid intercellular signaling in the central nervous system and occurs at synapses within gray matter. Here we show that action potentials also induce the release of glutamate from axons in the corpus callosum, a white matter region responsible for interhemispheric communication. Callosal axons release glutamate by vesicular fusion, which induces quantal AMPA receptor–mediated currents in NG2+ glial progenitors at anatomically distinct axo–glial synaptic junctions. Glutamate release from axons was facilitated by repetitive stimulation and could be inhibited through activation of metabotropic autoreceptors. Although NG2+ cells form associations with nodes of Ranvier in white matter, measurements of conduction velocity indicated that unmyelinated fibers are responsible for glutamatergic signaling with NG2+ glia. This activity-dependent secretion of glutamate was prevalent in the developing and mature mouse corpus callosum, indicating that axons within white matter both conduct action potentials and engage in rapid neuron-glia communication.

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Figure 1: NG2+ cells express DsRed in NG2-DsRed BAC mice.
Figure 2: Spontaneous release of glutamate within the corpus callosum activates AMPA receptors in NG2+ glial cells.
Figure 3: Stimulation of axons within the corpus callosum evokes the release of glutamate.
Figure 4: AMPAR currents in callosal NG2+ cells arise from vesicular release of glutamate.
Figure 5: AMPAR currents in NG2+ cells are not produced by reversed cycling of glutamate transporters or by vesicular release from astrocytes.
Figure 6: Axons form defined synaptic junctions with NG2+ cells within the corpus callosum.
Figure 7: Glutamate is released from unmyelinated axons in the corpus callosum.
Figure 8: NG2+ cells in the adult corpus callosum express Ca2+-permeable AMPARs.

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Acknowledgements

We thank N. Heintz (Columbia University, New York) for providing BAC cloning reagents, B. Glick (University of Chicago) for the DsRed-T1 cDNA, W.B. Stallcup (Burnham Institute, San Diego) for antibodies to NG2 and PDGFαR, M.H. Bhat (University of North Carolina, Chapel Hill) for antibodies to Caspr, R. Edwards (University of California, San Francisco) for VGLUT1+/+ and VGLUT1−/− tissue, N. Nishiyama for assistance with PCR and mouse breeding, the IVAX Drug Research Institute for GYKI 53655, G. Ellis-Davies for MNI-D-aspartate, M. Watanabe for support and comments on the manuscript, J. Egen for assistance with confocal imaging and image analysis, and P. Somogyi for comments on the manuscript. This work was supported by the US National Institutes of Health grants NS051509 (D.E.B.), PAR-02-059 (D.E.B.) and NS049267 (A.N.), as well as by the March of Dimes (D.E.B.), NARSAD (D.E.B.), the National Multiple Sclerosis Society (A.N.) and the Medical Scientist Training Program (J.L.Z.).

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  1. Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe St., WBSB 813, Baltimore, 21205, Maryland, USA

    Jennifer L Ziskin & Dwight E Bergles

  2. Department of Neurobiology and Physiology, University of Connecticut, 75 North Eagleville Road, Unit 3156, Storrs, 06269-3156, Connecticut, USA

    Akiko Nishiyama & Maria Rubio

  3. Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan

    Masahiro Fukaya

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Correspondence to Dwight E Bergles.

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Supplementary information

Supplementary Fig. 1

NMDA receptor expression by NG2+ cells in the corpus callosum. (PDF 196 kb)

Supplementary Fig. 2

Association of NG2+ cells with nerve terminals and nodes of Ranvier. (PDF 242 kb)

Supplementary Methods (PDF 67 kb)

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Ziskin, J., Nishiyama, A., Rubio, M. et al. Vesicular release of glutamate from unmyelinated axons in white matter. Nat Neurosci 10, 321–330 (2007). https://doi.org/10.1038/nn1854

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