Original Article

Role of n-type voltage-dependent calcium channels in autoimmune optic neuritis†

  1. Ivana Gadjanski PhD1,2,‡,
  2. Susann Boretius PhD3,‡,
  3. Sarah K. Williams PhD4,‡,
  4. Paul Lingor MD1,5,
  5. Johanna Knöferle MD1,
  6. Muriel B. Sättler MD1,
  7. Richard Fairless PhD4,
  8. Sonja Hochmeister MD, PhD6,
  9. Kurt-Wolfram Sühs MD4,
  10. Thomas Michaelis PhD3,
  11. Jens Frahm PhD3,
  12. Maria K. Storch MD6,
  13. Mathias Bähr MD1,5,
  14. Ricarda Diem MD4,*

Article first published online: 23 MAR 2009

DOI: 10.1002/ana.21668

Issue

Annals of Neurology

Annals of Neurology

Volume 66, Issue 1, pages 81–93, July 2009

Additional Information

How to Cite

Gadjanski, I., Boretius, S., Williams, S. K., Lingor, P., Knöferle, J., Sättler, M. B., Fairless, R., Hochmeister, S., Sühs, K.-W., Michaelis, T., Frahm, J., Storch, M. K., Bähr, M. and Diem, R. (2009), Role of n-type voltage-dependent calcium channels in autoimmune optic neuritis. Ann Neurol., 66: 81–93. doi: 10.1002/ana.21668

Author Information

  1. 1

    Department of Neurology, Georg-August University, Göttingen, Germany

  2. 2

    Department of Neurobiology, Institute for Biological Research, Sinisa Stankovic, Belgrade, Serbia

  3. 3

    Biomedizinische Nuclear Magnetic Resonance (NMR) Forschungs GmbH am Max-Planck Institut für biophysikalische Chemie, Göttingen, Germany

  4. 4

    Department of Neurology, University of the Saarland, Homburg/Saar, Germany

  5. 5

    Deutsche Forschungsgemeinschaft (DFG)-Research Center for Molecular Physiology of the Brain, Göttingen, Germany

  6. 6

    Department of Neurology, Medical University of Graz, Graz, Austria

  1. ‡

    I.G., S.B., and S.K.W. contributed equally to this work.

*Department of Neurology, University of the Saarland, Kirrberger Strasse, Building 90, 66421 Homburg/Saar, Germany

  1. †

    Potential conflict of interest: Nothing to report.

Publication History

  1. Issue published online: 10 AUG 2009
  2. Article first published online: 23 MAR 2009
  3. Accepted manuscript online: 23 MAR 2009 12:00AM EST
  4. Manuscript Accepted: 30 JAN 2009
  5. Manuscript Revised: 25 JAN 2009
  6. Manuscript Received: 14 JUL 2008

Funded by

  • 6th Framework Program of the European Union, NeuroproMiSe. Grant Number: LSHM-CT-2005-018637
  • Medical Faculty of the University of Göttingen (Junior Research Group Program)
  • Serbian Ministry of Science. Grant Number: 143005

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Abstract

Objective

The aim of this study was to investigate the role of voltage-dependent calcium channels (VDCCs) in axon degeneration during autoimmune optic neuritis.

Methods

Calcium ion (Ca2+) influx into the optic nerve (ON) through VDCCs was investigated in a rat model of optic neuritis using manganese-enhanced magnetic resonance imaging and in vivo calcium imaging. After having identified the most relevant channel subtype (N-type VDCCs), we correlated immunohistochemistry of channel expression with ON histopathology. In the confirmatory part of this work, we performed a treatment study using ω-conotoxin GVIA, an N-type specific blocker.

Results

We observed that pathological Ca2+ influx into ONs during optic neuritis is mediated via N-type VDCCs. By analyzing the expression of VDCCs in the inflamed ONs, we detected an upregulation of α1B, the pore-forming subunit of N-type VDCCs, in demyelinated axons. However, high expression levels were also found on macrophages/activated microglia, and lower levels were detected on astrocytes. The relevance of N-type VDCCs for inflammation-induced axonal degeneration and the severity of optic neuritis was corroborated by treatment with ω-conotoxin GVIA. This blocker led to decreased axon and myelin degeneration in the ONs together with a reduced number of macrophages/activated microglia. These protective effects were confirmed by analyzing the spinal cords of the same animals.

Interpretation

We conclude that N-type VDCCs play an important role in inflammation-induced axon degeneration via two mechanisms: First, they directly mediate toxic Ca2+ influx into the axons; and second, they contribute to macrophage/microglia function, thereby promoting secondary axonal damage. Ann Neurol 2009;66:81–93

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