Inadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibility

Handle URI:
http://hdl.handle.net/10754/626412
Title:
Inadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibility
Authors:
Kilic, Kivilcim; Karatas, Hulya; Donmez-Demir, Buket; Eren-Kocak, Emine; Gursoy-Ozdemir, Yasemin; Can, Alp; Petit, Jean-Marie; Magistretti, Pierre J. ( 0000-0002-6678-320X ) ; Dalkara, Turgay
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.
KAUST Department:
King Abdullah University of Science and Technology (KAUST) - Thuwal - Saudi Arabia and Brain Mind Institute, EPFL; Lausanne Switzerland
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.
Publisher:
Wiley-Blackwell
Journal:
Annals of Neurology
Issue Date:
16-Dec-2017
DOI:
10.1002/ana.25122
Type:
Article
ISSN:
0364-5134
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.).
Additional Links:
http://onlinelibrary.wiley.com/doi/10.1002/ana.25122/abstract
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Full metadata record

DC FieldValue Language
dc.contributor.authorKilic, Kivilcimen
dc.contributor.authorKaratas, Hulyaen
dc.contributor.authorDonmez-Demir, Buketen
dc.contributor.authorEren-Kocak, Emineen
dc.contributor.authorGursoy-Ozdemir, Yaseminen
dc.contributor.authorCan, Alpen
dc.contributor.authorPetit, Jean-Marieen
dc.contributor.authorMagistretti, Pierre J.en
dc.contributor.authorDalkara, Turgayen
dc.date.accessioned2017-12-21T13:57:04Z-
dc.date.available2017-12-21T13:57:04Z-
dc.date.issued2017-12-16en
dc.identifier.citationKilic 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.en
dc.identifier.issn0364-5134en
dc.identifier.doi10.1002/ana.25122en
dc.identifier.urihttp://hdl.handle.net/10754/626412-
dc.description.abstractGlycogen 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.en
dc.description.sponsorshipWe 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.).en
dc.publisherWiley-Blackwellen
dc.relation.urlhttp://onlinelibrary.wiley.com/doi/10.1002/ana.25122/abstracten
dc.rightsThis is the peer reviewed version of the following article: Inadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibility, which has been published in final form at http://doi.org/10.1002/ana.25122. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.en
dc.titleInadequate Brain Glycogen or Sleep Increases Spreading Depression Susceptibilityen
dc.typeArticleen
dc.contributor.departmentKing Abdullah University of Science and Technology (KAUST) - Thuwal - Saudi Arabia and Brain Mind Institute, EPFL; Lausanne Switzerlanden
dc.identifier.journalAnnals of Neurologyen
dc.eprint.versionPost-printen
dc.contributor.institutionInstitute of Neurological Sciences and Psychiatry, Hacettepe University; Ankara Turkeyen
dc.contributor.institutionDepartment of Histology and Embryology, School of Medicine; Ankara University; Ankara Turkeyen
dc.contributor.institutionCenter for Psychiatric Neuroscience, Department of Psychiatry; CHUV; Prilly Switzerlanden
dc.contributor.institutionDepartment of Neurology, Faculty of Medicine; Institute of Neurological Sciences and Psychiatry, Hacettepe University; Ankara Turkeyen
kaust.authorMagistretti, Pierre J.en
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