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    Inadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibility

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    Kilic_et_al-2017-Annals_of_Neurology.pdf
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    Type
    Article
    Authors
    Kilic, Kivilcim
    Karatas, Hulya
    Donmez-Demir, Buket
    Eren-Kocak, Emine
    Gursoy-Ozdemir, Yasemin
    Can, Alp
    Petit, Jean-Marie
    Magistretti, Pierre J. cc
    Dalkara, Turgay
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    King Abdullah University of Science and Technology (KAUST) - Thuwal - Saudi Arabia and Brain Mind Institute, EPFL; Lausanne Switzerland
    Date
    2018-01-24
    Online Publication Date
    2018-01-24
    Print Publication Date
    2018-01
    Permanent link to this record
    http://hdl.handle.net/10754/626412
    
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    Abstract
    Glycogen in astrocyte endfeet contributes to maintenance of low extracellular glutamate and K+ concentrations around synapses. Sleep deprivation (SD), a common migraine trigger induces transcriptional changes in astrocytes reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K+ can rise to levels that activate neuronal pannexin-1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches.We suppressed glycogen breakdown by inhibiting glycogen phosphorylation with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and by SD.DAB caused neuronal pannexin-1 large-pore opening and activation of the downstream inflammatory pathway as shown by procaspase-1 cleavage and HMGB1 release from neurons. Six-hour SD induced pannexin-1 mRNA. DAB and SD also lowered the cortical spreading depression (CSD) induction threshold, which was reversed by glucose or lactate supplement, suggesting that glycogen-derived energy substrates are needed to prevent CSD generation. Supporting this, knocking-down neuronal lactate transporter, MCT2 with an anti-sense oligonucleotide or inhibiting glucose transport from vessels to astrocytes with intracerebroventricularly given phloretin reduced the CSD threshold. In vivo recordings with a K+ -sensitive/selective fluoroprobe, APG-4 disclosed that DAB treatment or SD caused significant rise in extracellular K+ during whisker-stimulation, illustrating the critical role of glycogen in extracellular K+ clearance.Synaptic metabolic stress caused by insufficient glycogen-derived energy substrate supply can activate neuronal pannexin-1 channels as well as lowering the CSD threshold. Therefore, conditions that limit energy supply to synapse (e.g. SD) may predispose to migraine attacks as suggested by genetic studies associating glucose or lactate transporter deficiency with migraine. This article is protected by copyright. All rights reserved.
    Citation
    Kilic K, Karatas H, Donmez-Demir B, Eren-Kocak E, Gursoy-Ozdemir Y, et al. (2017) Inadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibility. Annals of Neurology. Available: http://dx.doi.org/10.1002/ana.25122.
    Sponsors
    We are grateful to M. Yilmaz for his expert help with Western blotting and Sahin Hanalioğlu for his advises on APG-4 experiments and Mr. Joël Gyger for his excellent technical expertise in RTPCR experiments. We thank to Deniz Ashan Madencioglu and Burak Uzay for their help with sleep deprivation experiments. This work was supported by the Turkish Academy of Sciences (T.D.) and Hacettepe University Research Fund 013 D07 105 001-258 (T.D.) and Swiss National Science Foundation grant 3100AO-108336/1 (P.J.M.).
    Publisher
    Wiley
    Journal
    Annals of Neurology
    DOI
    10.1002/ana.25122
    PubMed ID
    29244233
    Additional Links
    http://onlinelibrary.wiley.com/doi/10.1002/ana.25122/abstract
    ae974a485f413a2113503eed53cd6c53
    10.1002/ana.25122
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program

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