Original Article

High cortical spreading depression susceptibility and migraine-associated symptoms in Cav2.1 S218L mice

  1. Arn M. J. M. van den Maagdenberg PhD1,2,‡,*,
  2. Tommaso Pizzorusso PhD3,‡,
  3. Simon Kaja PhD2,4,†,‡,
  4. Nicole Terpolilli MD5,‡,
  5. Maryna Shapovalova PhD6,7,
  6. Freek E. Hoebeek PhD8,
  7. Curtis F. Barrett PhD1,2,
  8. Lisa Gherardini PhD3,
  9. Rob C. G. van de Ven PhD1,
  10. Boyan Todorov MS, PharmD1,
  11. Ludo A. M. Broos BSc1,
  12. Angelita Tottene PhD6,7,
  13. Zhenyu Gao MSc8,
  14. Mariann Fodor PhD9,§,
  15. Chris I. De Zeeuw MD, PhD8,10,
  16. Rune R. Frants PhD1,
  17. Nikolaus Plesnila PhD5,
  18. Jaap J. Plomp PhD2,4,
  19. Daniela Pietrobon PhD6,7,*,
  20. Michel D. Ferrari MD, PhD2

Article first published online: 4 AUG 2009

DOI: 10.1002/ana.21815

Issue

Annals of Neurology

Annals of Neurology

Volume 67, Issue 1, pages 85–98, January 2010

Additional Information

How to Cite

van den Maagdenberg, A. M. J. M., Pizzorusso, T., Kaja, S., Terpolilli, N., Shapovalova, M., Hoebeek, F. E., Barrett, C. F., Gherardini, L., van de Ven, R. C. G., Todorov, B., Broos, L. A. M., Tottene, A., Gao, Z., Fodor, M., De Zeeuw, C. I., Frants, R. R., Plesnila, N., Plomp, J. J., Pietrobon, D. and Ferrari, M. D. (2010), High cortical spreading depression susceptibility and migraine-associated symptoms in Cav2.1 S218L mice. Annals of Neurology, 67: 85–98. doi: 10.1002/ana.21815

Author Information

  1. 1

    Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands

  2. 2

    Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands

  3. 3

    Department of Psychology, University of Firenze and CNR Institute of Neuroscience, Pisa, Italy

  4. 4

    Department of Molecular Cell Biology–Section Neurophysiology, Leiden University Medical Centre, Leiden, The Netherlands

  5. 5

    Department of Neurosurgery and Institute for Surgical Research, University of Munich Medical Centre–Grosshadern, Munich, Germany

  6. 6

    Department of Biomedical Sciences, University of Padova, Italy

  7. 7

    CNR Institute of Neuroscience, Padova, Italy

  8. 8

    Department of Neuroscience, Erasmus Medical Centre, Rotterdam, The Netherlands

  9. 9

    Department of Embryology and Anatomy, Leiden University Medical Centre, Leiden, The Netherlands

  10. 10

    Netherlands Institute for Neuroscience, Royal Dutch Academy for Sciences (KNAW), Amsterdam, The Netherlands

  1. †

    Department of Ophthalmology, University of Missouri–Kansas City, School of Medicine, Kansas City, MO

  1. ‡

    A.M.J.M.v.d.M., T.P., S.K., and N.T. contributed equally to this article.

  2. §

    Dr Mariann Fodor is deceased.

*Department of Human Genetics, Leiden University Medical Centre, Einthovenweg 20, PO Box 9600, Leiden, The Netherlands

Publication History

  1. Issue published online: 23 FEB 2010
  2. Article first published online: 4 AUG 2009
  3. Accepted manuscript online: 4 AUG 2009 12:00AM EST
  4. Manuscript Accepted: 28 JUL 2009
  5. Manuscript Revised: 8 JUL 2009
  6. Manuscript Received: 22 OCT 2008

Funded by

  • Netherlands Organization for Scientific Research (NWO). Grant Numbers: 903-52-291, Vici 918.56.602
  • EU “EUROHEAD”. Grant Number: LSHM-CT-2004-504837
  • Center of Medical System Biology established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research and Community
  • Telethon Italy. Grant Number: GGP05236
  • Italian Ministry of Education University Research. Grant Numbers: PRIN2005, FIRB2002
  • Prinses Beatrix Fonds. Grant Number: MAR01-0105
  • Hersenstichting Nederland. Grant Number: 9F01(2).24
  • KNAW van Leersumfonds. Grant Number: AFD/ML/2901
  • Dutch ZON-MW Organization for Medical Sciences. Grant Number: 912-07-022
  • ALW Life Sciences, Senter (Neuro-Bsik). Grant Number: BSIK03053
  • Prinses Beatrix Fonds. Grant Number: OP05-16/100506
  • SENSOPAC program of the European Community. Grant Number: 028056
  • European Molecular Biology Organization postdoctoral fellowship. Grant Number: ALTF810-2005
  • Michael Smith Foundation for Health Research trainee award. Grant Number: ST-PDF-00140[05-1]BM

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Abstract

Objective

The CACNA1A gene encodes the pore-forming subunit of neuronal CaV2.1 Ca2+ channels. In patients, the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome that is associated with ataxia, seizures, and severe, sometimes fatal, brain edema often triggered by only a mild head trauma.

Methods

We introduced the S218L mutation into the mouse Cacna1a gene and studied the mechanisms for the S218L syndrome by analyzing the phenotypic, molecular, and electrophysiological consequences.

Results

Cacna1aS218L mice faithfully mimic the associated clinical features of the human S218L syndrome. S218L neurons exhibit a gene dosage–dependent negative shift in voltage dependence of CaV2.1 channel activation, resulting in enhanced neurotransmitter release at the neuromuscular junction. Cacna1aS218L mice also display an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus. In contrast, mice bearing the R192Q CACNA1A mutation, which in humans causes a milder form of hemiplegic migraine, typically exhibit only a single CSD event after one triggering stimulus.

Interpretation

The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema. ANN NEUROL 2010;67:85–98

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