1. Medicine
  2. Neuroscience

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
https://doi.org/10.7554/eLife.74923
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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

Version 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)
  6. Version of Record updated: June 27, 2023 (version 3)

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.

Metrics

  • 620
    Page views
  • 97
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organism

Further reading

    1. Medicine
    2. Stem Cells and Regenerative Medicine

    Multiomics analyses reveal dynamic bioenergetic pathways and functional remodeling of the heart during intermittent fasting

    Thiruma V Arumugam, Asfa Alli-Shaik ... Jayantha Gunaratne
    Research Article

    Intermittent fasting (IF) has been shown to reduce cardiovascular risk factors in both animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction. However, the underlying molecular mechanisms behind these effects remain unclear. To shed light on the molecular and cellular adaptations of the heart to IF, we conducted comprehensive system-wide analyses of the proteome, phosphoproteome, and transcriptome, followed by functional analysis. Using advanced mass spectrometry, we profiled the proteome and phosphoproteome of heart tissues obtained from mice that were maintained on daily 12- or 16 hr fasting, every-other-day fasting, or ad libitum control feeding regimens for 6 months. We also performed RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. Our analyses revealed that IF significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Furthermore, we found that the impact of IF on different metabolic processes varied depending on the length of the fasting regimen. Short IF regimens showed a higher correlation of pathway alteration, while longer IF regimens had an inverse correlation of metabolic processes such as fatty acid oxidation and immune processes. Additionally, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. Our systematic multi-omics study provides a molecular framework for understanding how IF impacts the heart’s function and its vulnerability to injury and disease.

    1. Medicine

    SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury

    Xiaoyan Yang, Hsiang-Chun Chang ... Hossein Ardehali
    Research Article

    Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

    1. Medicine

    An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo

    Luyang Cao, Lixiang Ma ... Jingsong Xu
    Research Article

    Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.