Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition
- University of Illinois at Chicago, United States
- University of Colorado Anschutz Medical Campus, United States
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.
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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.
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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Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition
eLife 10:e63076.
https://doi.org/10.7554/eLife.63076
