Inadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibility
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ArticleAuthors
Kilic, KivilcimKaratas, Hulya
Donmez-Demir, Buket
Eren-Kocak, Emine
Gursoy-Ozdemir, Yasemin
Can, Alp
Petit, Jean-Marie
Magistretti, Pierre J.

Dalkara, Turgay
KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
King Abdullah University of Science and Technology (KAUST) - Thuwal - Saudi Arabia and Brain Mind Institute, EPFL; Lausanne Switzerland
Date
2018-01-24Online Publication Date
2018-01-24Print Publication Date
2018-01Permanent link to this record
http://hdl.handle.net/10754/626412
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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
WileyJournal
Annals of NeurologyPubMed ID
29244233Additional Links
http://onlinelibrary.wiley.com/doi/10.1002/ana.25122/abstractae974a485f413a2113503eed53cd6c53
10.1002/ana.25122
Scopus Count
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