Neuronal complexity is attenuated in preclinical models of migraine and restored by hdac6 inhibition

Zachariah Bertels, Harinder Singh, Isaac Dripps, Kendra Siegersma, Alycia F. Tipton, Wiktor Witkowski, Zoie Sheets, Pal Shah, Catherine Conway, Elizaveta Mangutov, Mei Ao, Valentina Petukhova, Bhargava Karumudi, Pavel A. Petukhov, Serapio M. Baca, Mark M. Rasenick, Amynah A. Pradhan

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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. Histonedeacetylase-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.

Original languageEnglish
Article numbere63076
StatePublished - Apr 2021


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