The molecular physiology of the axo-myelinic synapse

Ileana Micu, Jason R Plemel, Celia Lachance, Juliane Proft, Andrew J Jansen, Karen Cummins, Jan van Minnen, Peter K Stys

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo-myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis.

LanguageEnglish
Pages41-50
Number of pages10
JournalExperimental Neurology
Volume276
Early online date26 Oct 2015
DOIs
Publication statusPublished - Feb 2016
Externally publishedYes

Fingerprint

Myelin Sheath
Synapses
Axons
Optic Nerve
Action Potentials
Glutamic Acid
Tetanus Toxin
Ryanodine Receptor Calcium Release Channel
Central Nervous System Diseases
Demyelinating Diseases
N-Methyl-D-Aspartate Receptors
Photons
Neuroglia
Electric Stimulation
Multiple Sclerosis
Microscopy
Schizophrenia
Communication
Learning

Keywords

  • Myelin
  • Axons/physiology
  • Calcium Signaling/physiology
  • Multi photon microscopy
  • Mice
  • Mice, Knockout
  • Myelin Sheath/physiology
  • Nerve Fibers, Myelinated/physiology
  • Optic Nerve/physiology
  • Rats
  • Rats, Long-Evans
  • Receptors, N-Methyl-D-Aspartate/physiology
  • Synapses/physiology

Cite this

Micu, I., Plemel, J. R., Lachance, C., Proft, J., Jansen, A. J., Cummins, K., ... Stys, P. K. (2016). The molecular physiology of the axo-myelinic synapse. Experimental Neurology, 276, 41-50. https://doi.org/10.1016/j.expneurol.2015.10.006
Micu, Ileana ; Plemel, Jason R ; Lachance, Celia ; Proft, Juliane ; Jansen, Andrew J ; Cummins, Karen ; van Minnen, Jan ; Stys, Peter K. / The molecular physiology of the axo-myelinic synapse. In: Experimental Neurology. 2016 ; Vol. 276. pp. 41-50.
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abstract = "Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo-myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis.",
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Micu, I, Plemel, JR, Lachance, C, Proft, J, Jansen, AJ, Cummins, K, van Minnen, J & Stys, PK 2016, 'The molecular physiology of the axo-myelinic synapse', Experimental Neurology, vol. 276, pp. 41-50. https://doi.org/10.1016/j.expneurol.2015.10.006

The molecular physiology of the axo-myelinic synapse. / Micu, Ileana; Plemel, Jason R; Lachance, Celia; Proft, Juliane; Jansen, Andrew J; Cummins, Karen; van Minnen, Jan; Stys, Peter K.

In: Experimental Neurology, Vol. 276, 02.2016, p. 41-50.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The molecular physiology of the axo-myelinic synapse

AU - Micu, Ileana

AU - Plemel, Jason R

AU - Lachance, Celia

AU - Proft, Juliane

AU - Jansen, Andrew J

AU - Cummins, Karen

AU - van Minnen, Jan

AU - Stys, Peter K

N1 - Copyright © 2015 Elsevier Inc. All rights reserved.

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Y1 - 2016/2

N2 - Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo-myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis.

AB - Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo-myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis.

KW - Myelin

KW - Axons/physiology

KW - Calcium Signaling/physiology

KW - Multi photon microscopy

KW - Mice

KW - Mice, Knockout

KW - Myelin Sheath/physiology

KW - Nerve Fibers, Myelinated/physiology

KW - Optic Nerve/physiology

KW - Rats

KW - Rats, Long-Evans

KW - Receptors, N-Methyl-D-Aspartate/physiology

KW - Synapses/physiology

U2 - 10.1016/j.expneurol.2015.10.006

DO - 10.1016/j.expneurol.2015.10.006

M3 - Article

VL - 276

SP - 41

EP - 50

JO - Experimental Neurology

T2 - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

ER -

Micu I, Plemel JR, Lachance C, Proft J, Jansen AJ, Cummins K et al. The molecular physiology of the axo-myelinic synapse. Experimental Neurology. 2016 Feb;276:41-50. https://doi.org/10.1016/j.expneurol.2015.10.006