Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic migraine 1 increase the susceptibility for cortical spreading depolarization and seizures and worsen outcome after experimental traumatic brain injury

  1. Nicole A Terpollili
  2. Reinhard Dolp
  3. Kai Waehner
  4. Susanne M Schwarzmaier
  5. Elisabeth Rumbler
  6. Boyan Todorov
  7. Michel D Ferrari
  8. Arn MJM van dem Maagdenburg
  9. Nikolaus Plesnila  Is a corresponding author
  1. Ludwig Maximilian University of Munich (LMU), Germany
  2. Mannheim University, Germany
  3. Leiden University Medical Center, Netherlands

Abstract

Patients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected knock-in mice carrying the severer S218L or milder R192Q FHM1 gain-of-function missense mutation in the CACNA1A gene that encodes the α1A subunit of neuronal voltage-gated CaV2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact (CCI) and investigated cortical spreading depolarizations (CSDs), lesion volume, brain edema formation, and functional outcome. After TBI, all mutant mice displayed considerably more CSDs and seizures than WT mice, while S218L mutant mice had a substantially higher mortality. Brain edema formation and the resulting increase in intracranial pressure was more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here we show that gain of CaV2.1 channel function worsens histopathological and functional outcome after TBI in mice. This phenotype was associated with a higher number of CSDs, increased seizure activity, and more pronounced brain edema formation. Hence, our results suggest increased susceptibility for CSDs and seizures as potential mechanisms for bad outcome after TBI in FHM1 mutation carriers.

Data availability

All data generated or analyzed during this study are included in the manuscript. Source Data are available for all figures. A link to a data repository (OSF.io) is provided in the manuscript.

Article and author information

Author details

  1. Nicole A Terpollili

    Institute for Stroke and Dementia Research, Ludwig Maximilian University of Munich (LMU), Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7070-3113
  2. Reinhard Dolp

    Department of Neurosurgery, Ludwig Maximilian University of Munich (LMU), Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Kai Waehner

    Department of Neurosurgery, Mannheim University, Mannheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Susanne M Schwarzmaier

    Institute for Stroke and Dementia Research, Ludwig Maximilian University of Munich (LMU), Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Elisabeth Rumbler

    Department of Neurosurgery, Ludwig Maximilian University of Munich (LMU), Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Boyan Todorov

    Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Michel D Ferrari

    Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Arn MJM van dem Maagdenburg

    Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Nikolaus Plesnila

    Institute for Stroke and Dementia Research, Ludwig Maximilian University of Munich (LMU), Munich, Germany
    For correspondence
    Nikolaus.Plesnila@med.uni-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8832-228X

Funding

University of Munich FoeFoLe Program (#669)

  • Nicole A Terpollili

Netherlands Organization for Scientific Research (918.56.602)

  • Arn MJM van dem Maagdenburg

Centre of Medical System Biology (050-060-409)

  • Arn MJM van dem Maagdenburg

European Community (FP7-EUROHEADPAIN)

  • Arn MJM van dem Maagdenburg

Deutsche Forschungsgemeinschaft (EXC 2145 SyNergy - ID 390857198)

  • Nikolaus Plesnila

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was reviewed by the Ethics Board and approved by the Veterinary Office of the Government of Upper Bavaria (protocol # 118/05). All of the animals were handled according to approved institutional animal care protocols. All surgery was performed in deep inhalation anesthesia and animals received appropriate analgesia post-surgery. Every effort was made to minimize suffering.

Reviewing Editor

  1. Mark T Nelson, University of Vermont, United States

Publication history

  1. Received: October 21, 2021
  2. Preprint posted: December 2, 2021 (view preprint)
  3. Accepted: March 2, 2022
  4. Accepted Manuscript published: March 3, 2022 (version 1)
  5. Version of Record published: March 14, 2022 (version 2)

Copyright

© 2022, Terpollili et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nicole A Terpollili
  2. Reinhard Dolp
  3. Kai Waehner
  4. Susanne M Schwarzmaier
  5. Elisabeth Rumbler
  6. Boyan Todorov
  7. Michel D Ferrari
  8. Arn MJM van dem Maagdenburg
  9. Nikolaus Plesnila
(2022)
Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic migraine 1 increase the susceptibility for cortical spreading depolarization and seizures and worsen outcome after experimental traumatic brain injury
eLife 11:e74923.
https://doi.org/10.7554/eLife.74923

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    Supported by National Institutes of Health R01 HL122352 grant; ‘la Caixa’ Banking Foundation (HR18-00304); Fundación La Marató TV3: Ayudas a la investigación en enfermedades raras 2020 (LA MARATO-2020); Instituto de Salud Carlos III/FEDER/FSE; Horizon 2020 - Research and Innovation Framework Programme GA-965286 to JJ; the CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation), and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). American Heart Association postdoctoral fellowship 19POST34380706s to JVEN. Israel Science Foundation to OB and MA [824/19]. Rappaport grant [01012020RI]; and Niedersachsen Foundation [ZN3452] to OB; US-Israel Binational Science Foundation (BSF) to OB and TH [2019039]; Dr. Bernard Lublin Donation to OB; and The Duchenne Parent Project Netherlands (DPPNL 2029771) to OB. National Institutes of Health R01 AR068428 to DM and US-Israel Binational Science Foundation Grant [2013032] to DM and OB.