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Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

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Cite this article as: eLife 2021;10:e63076 doi: 10.7554/eLife.63076

Abstract

Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Zachariah Bertels

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Harinder Singh

    Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0160-1575
  3. Isaac Dripps

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kendra Siegersma

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alycia F Tipton

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Wiktor D Witkowski

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Zoie Sheets

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Pal Shah

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Catherine Conway

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Elizaveta Mangutov

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Mei Ao

    Physiology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Valentina Petukhova

    Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Bhargava Karumudi

    Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Pavel A Petukhov

    Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Serapio M Baca

    Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Mark M Rasenick

    Physiology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Amynah A Pradhan

    Psychiatry, University of Illinois at Chicago, Chicago, United States
    For correspondence
    Pradhan4@uic.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9691-2976

Funding

National Institute of Neurological Disorders and Stroke (NS109862)

  • Amynah A Pradhan

National Institute on Drug Abuse (DA040688)

  • Amynah A Pradhan

National Center for Complementary and Integrative Health (AT009169)

  • Mark M Rasenick

Center for Integrated Healthcare, U.S. Department of Veterans Affairs (BX00149)

  • Mark M Rasenick

Amgen Foundation

  • Amynah A Pradhan

Center for Clinical and Translational Science, University of Illinois at Chicago

  • Amynah A Pradhan

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 performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#18-250) of the University of Illinois at Chicago.

Reviewing Editor

  1. Allan Basbaum, University of California San Francisco, United States

Publication history

  1. Received: September 14, 2020
  2. Accepted: April 12, 2021
  3. Accepted Manuscript published: April 15, 2021 (version 1)
  4. Version of Record published: May 17, 2021 (version 2)

Copyright

© 2021, Bertels 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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