{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:19:12Z","timestamp":1782937152404,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012959","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000}}],"reference-count":102,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T00:00:00Z","timestamp":1743724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020899","name":"Board of the Swiss Federal Institutes of Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020899","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Disruptions of energy supply to the brain are associated with many neurodegenerative pathologies and are difficult to study due to numerous interlinked metabolic pathways. We explored the effects of diminished energy supply on brain metabolism using a computational model of the neuro-glia-vasculature ensemble, in the form of a neuron, an astrocyte and local blood supply. As a case study, we investigated the glucose transporter type-1 deficiency syndrome (GLUT1-DS), a childhood affliction characterized by impaired glucose utilization and associated with phenotypes including seizures. Compared to neurons, astrocytes exhibited markedly higher metabolite concentration variabilities for all but a few redox species. This effect could signal a role for astrocytes in absorbing the shock of blood nutrient fluctuations. Redox balances were disrupted in GLUT1-DS with lower levels of reducing equivalent carriers NADH and ATP. The best non-glucose nutrient or pharmacotherapies for re-establishing redox normalcy involved lactate, the keto-diet (\u03b2-hydroxybutyrate), NAD and Q10 supplementation, suggesting a possible glucose sparing mechanism. GLUT1-DS seizures resulted from after-discharge neuronal firing caused by post-stimulus ATP reductions and impaired Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>-ATPase, which can be rescued by restoring either normal glucose or by relatively small increases in neuronal ATP.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012959","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T18:14:29Z","timestamp":1743790469000},"page":"e1012959","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Seizure and redox rescue in a model of glucose transport deficiency"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2270-1989","authenticated-orcid":true,"given":"Jay S.","family":"Coggan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2574-1732","authenticated-orcid":true,"given":"Polina","family":"Shichkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Markram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,4]]},"reference":[{"issue":"11","key":"pcbi.1012959.ref001","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1080\/1071576021000016391","article-title":"Oxidative stress, mitochondrial dysfunction, and epilepsy","volume":"36","author":"MN Patel","year":"2002","journal-title":"Free Radic Res"},{"issue":"4","key":"pcbi.1012959.ref002","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/ana.24014","article-title":"Energy failure: does it contribute to neurodegeneration?","volume":"74","author":"D Pathak","year":"2013","journal-title":"Ann Neurol"},{"issue":"6228","key":"pcbi.1012959.ref003","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1126\/science.aaa1299","article-title":"Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy","volume":"347","author":"N Sada","year":"2015","journal-title":"Science"},{"key":"pcbi.1012959.ref004","doi-asserted-by":"crossref","first-page":"105470","DOI":"10.1016\/j.nbd.2021.105470","article-title":"Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response","volume":"158","author":"RE Fulton","year":"2021","journal-title":"Neurobiol Dis"},{"issue":"2","key":"pcbi.1012959.ref005","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s11064-007-9471-1","article-title":"Metabolism of [U-13C]glutamine and [U-13C]glutamate in isolated rat brain mitochondria suggests functional phosphate-activated glutaminase activity in matrix","volume":"33","author":"LK Bak","year":"2008","journal-title":"Neurochem Res"},{"issue":"9","key":"pcbi.1012959.ref006","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/s41573-020-0072-x","article-title":"Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing","volume":"19","author":"SC Cunnane","year":"2020","journal-title":"Nat Rev Drug Discov"},{"issue":"4","key":"pcbi.1012959.ref007","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/s41574-021-00626-7","article-title":"Mitochondrial and metabolic dysfunction in ageing and age-related diseases","volume":"18","author":"JA Amorim","year":"2022","journal-title":"Nat Rev Endocrinol"},{"issue":"4","key":"pcbi.1012959.ref008","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1113\/expphysiol.2010.053157","article-title":"Neuron-glia metabolic coupling and plasticity","volume":"96","author":"PJ Magistretti","year":"2011","journal-title":"Exp Physiol"},{"issue":"8","key":"pcbi.1012959.ref009","doi-asserted-by":"crossref","first-page":"e1006392","DOI":"10.1371\/journal.pcbi.1006392","article-title":"Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate","volume":"14","author":"JS Coggan","year":"2018","journal-title":"PLoS Comput Biol"},{"issue":"6","key":"pcbi.1012959.ref010","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.cmet.2011.08.016","article-title":"Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation","volume":"14","author":"M B\u00e9langer","year":"2011","journal-title":"Cell Metab"},{"issue":"22","key":"pcbi.1012959.ref011","doi-asserted-by":"crossref","first-page":"10625","DOI":"10.1073\/pnas.91.22.10625","article-title":"Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization","volume":"91","author":"L Pellerin","year":"1994","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4\u20135","key":"pcbi.1012959.ref012","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1159\/000017324","article-title":"Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle","volume":"20","author":"L Pellerin","year":"1998","journal-title":"Dev Neurosci"},{"key":"pcbi.1012959.ref013","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.brainresbull.2017.12.010","article-title":"Brain activity-induced neuronal glucose uptake\/glycolysis: Is the lactate shuttle not required?","volume":"137","author":"BL Tang","year":"2018","journal-title":"Brain Res Bull"},{"issue":"12","key":"pcbi.1012959.ref014","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/glia.20528","article-title":"Activity-dependent regulation of energy metabolism by astrocytes: an update","volume":"55","author":"L Pellerin","year":"2007","journal-title":"Glia"},{"issue":"9","key":"pcbi.1012959.ref015","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1007\/s00424-020-02441-x","article-title":"Glucose transporters in brain in health and disease","volume":"472","author":"H Koepsell","year":"2020","journal-title":"Pflugers Arch"},{"issue":"10","key":"pcbi.1012959.ref016","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1056\/NEJM199109053251006","article-title":"Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay","volume":"325","author":"DC De Vivo","year":"1991","journal-title":"N Engl J Med"},{"issue":"6","key":"pcbi.1012959.ref017","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1212\/WNL.23.6.640","article-title":"Ketotic hypoglycemia and the ketogenic diet","volume":"23","author":"DC DeVivo","year":"1973","journal-title":"Neurology"},{"issue":"7","key":"pcbi.1012959.ref018","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.braindev.2009.02.008","article-title":"The expanding phenotype of GLUT1-deficiency syndrome","volume":"31","author":"K Brockmann","year":"2009","journal-title":"Brain Dev"},{"key":"pcbi.1012959.ref019","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.yebeh.2018.06.010","article-title":"The glucose transporter type 1 (Glut1) syndromes","volume":"91","author":"H Koch","year":"2019","journal-title":"Epilepsy Behav"},{"issue":"11","key":"pcbi.1012959.ref020","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1002\/jnr.23998","article-title":"Near-critical GLUT1 and Neurodegeneration","volume":"95","author":"LF Barros","year":"2017","journal-title":"J Neurosci Res"},{"issue":"6","key":"pcbi.1012959.ref021","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s10863-010-9321-8","article-title":"The potential role of mitochondrial dysfunction in seizure-associated cell death in the hippocampus and epileptogenesis","volume":"42","author":"S-D Chen","year":"2010","journal-title":"J Bioenerg Biomembr"},{"issue":"7","key":"pcbi.1012959.ref022","first-page":"532","article-title":"Epilepsy in Mitochondrial Diseases-Current State of Knowledge on Aetiology and Treatment","volume":"8","author":"D Wes\u00f3\u0142-Kucharska","year":"2021","journal-title":"Children (Basel)"},{"issue":"5","key":"pcbi.1012959.ref023","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S0197-4580(97)00111-5","article-title":"GLUT-1 expression in the cerebra of patients with Alzheimer\u2019s disease","volume":"18","author":"AD Mooradian","year":"1997","journal-title":"Neurobiol Aging"},{"issue":"9","key":"pcbi.1012959.ref024","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1002\/acn3.50881","article-title":"Therapeutic strategies for glucose transporter 1 deficiency syndrome","volume":"6","author":"M Tang","year":"2019","journal-title":"Ann Clin Transl Neurol"},{"issue":"3","key":"pcbi.1012959.ref025","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1111\/j.1471-4159.2008.05460.x","article-title":"The ketogenic diet increases mitochondrial glutathione levels","volume":"106","author":"SG Jarrett","year":"2008","journal-title":"J Neurochem"},{"key":"pcbi.1012959.ref026","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/j.1528-1167.2008.01833.x","article-title":"Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet","author":"J Klepper","year":"2008","journal-title":"Epilepsia"},{"issue":"11","key":"pcbi.1012959.ref027","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1194\/jlr.R048975","article-title":"Ketogenic diets, mitochondria, and neurological diseases","volume":"55","author":"LB Gano","year":"2014","journal-title":"J Lipid Res"},{"issue":"1","key":"pcbi.1012959.ref028","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00726-016-2336-7","article-title":"Control of seizures by ketogenic diet-induced modulation of metabolic pathways","volume":"49","author":"RM Clanton","year":"2017","journal-title":"Amino Acids"},{"issue":"665","key":"pcbi.1012959.ref029","doi-asserted-by":"crossref","first-page":"eabn2956","DOI":"10.1126\/scitranslmed.abn2956","article-title":"Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency","volume":"14","author":"K Rajasekaran","year":"2022","journal-title":"Sci Transl Med"},{"issue":"1","key":"pcbi.1012959.ref030","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/ana.20331","article-title":"Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects","volume":"57","author":"D Wang","year":"2005","journal-title":"Ann Neurol"},{"issue":"3","key":"pcbi.1012959.ref031","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/epi4.12414","article-title":"Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group","volume":"5","author":"J Klepper","year":"2020","journal-title":"Epilepsia Open"},{"issue":"4","key":"pcbi.1012959.ref032","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1136\/jnnp-2019-321694","article-title":"Transition from ketogenic diet to triheptanoin in patients with GLUT1 deficiency syndrome","volume":"91","author":"E Hainque","year":"2020","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"10","key":"pcbi.1012959.ref033","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1001\/jamaneurol.2014.1584","article-title":"Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement","volume":"71","author":"JM Pascual","year":"2014","journal-title":"JAMA Neurol"},{"issue":"11","key":"pcbi.1012959.ref034","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1002\/jnr.24111","article-title":"Triheptanoin for the treatment of brain energy deficit: A 14-year experience","volume":"95","author":"F Mochel","year":"2017","journal-title":"J Neurosci Res"},{"issue":"7","key":"pcbi.1012959.ref035","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1111\/epi.17263","article-title":"A randomized, double-blind trial of triheptanoin for drug-resistant epilepsy in glucose transporter 1 deficiency syndrome","volume":"63","author":"P Striano","year":"2022","journal-title":"Epilepsia"},{"issue":"7","key":"pcbi.1012959.ref036","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1111\/j.1469-8749.2011.03949.x","article-title":"Milder phenotypes of glucose transporter type 1 deficiency syndrome","volume":"53","author":"G Anand","year":"2011","journal-title":"Dev Med Child Neurol"},{"issue":"3","key":"pcbi.1012959.ref037","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1006\/nimg.2002.1224","article-title":"A model of the coupling between brain electrical activity, metabolism, and hemodynamics: application to the interpretation of functional neuroimaging","volume":"17","author":"A Aubert","year":"2002","journal-title":"Neuroimage"},{"key":"pcbi.1012959.ref038","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jtbi.2015.03.037","article-title":"A spatially distributed computational model of brain cellular metabolism","volume":"376","author":"D Calvetti","year":"2015","journal-title":"J Theor Biol"},{"issue":"2","key":"pcbi.1012959.ref039","doi-asserted-by":"crossref","first-page":"e1004036","DOI":"10.1371\/journal.pcbi.1004036","article-title":"Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble","volume":"11","author":"R Jolivet","year":"2015","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1012959.ref040","doi-asserted-by":"crossref","first-page":"120597","DOI":"10.1016\/j.jns.2023.120597","article-title":"Association between cerebrospinal fluid parameters and developmental and neurological status in glucose transporter 1 deficiency syndrome","volume":"447","author":"S Nabatame","year":"2023","journal-title":"J Neurol Sci"},{"issue":"6 Suppl 1","key":"pcbi.1012959.ref041","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1097\/01.nrl.0000340787.30542.41","article-title":"Epilepsy in inherited metabolic disorders","volume":"14","author":"JM Pascual","year":"2008","journal-title":"Neurologist"},{"issue":"5","key":"pcbi.1012959.ref042","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.pediatrneurol.2015.08.001","article-title":"Glucose Transporter Type I Deficiency (G1D) at 25 (1990-2015): Presumptions, Facts, and the Lives of Persons With This Rare Disease","volume":"53","author":"JM Pascual","year":"2015","journal-title":"Pediatr Neurol"},{"issue":"4","key":"pcbi.1012959.ref043","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1161\/CIRCRESAHA.119.316463","article-title":"Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity","volume":"127","author":"K Veys","year":"2020","journal-title":"Circ Res"},{"issue":"6","key":"pcbi.1012959.ref044","doi-asserted-by":"crossref","first-page":"ENEURO.0303-20.2020","DOI":"10.1523\/ENEURO.0303-20.2020","article-title":"Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain","volume":"7","author":"Y Zilberter","year":"2020","journal-title":"eNeuro"},{"issue":"1","key":"pcbi.1012959.ref045","doi-asserted-by":"crossref","first-page":"8951","DOI":"10.1038\/s41598-023-36001-x","article-title":"Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)","volume":"13","author":"A Avila","year":"2023","journal-title":"Sci Rep"},{"issue":"5","key":"pcbi.1012959.ref046","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1177\/0271678X221077343","article-title":"How expensive is the astrocyte?","volume":"42","author":"LF Barros","year":"2022","journal-title":"J Cereb Blood Flow Metab"},{"key":"pcbi.1012959.ref047","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3389\/fnins.2015.00023","article-title":"Methylglyoxal, the dark side of glycolysis","volume":"9","author":"I Allaman","year":"2015","journal-title":"Front Neurosci"},{"issue":"17","key":"pcbi.1012959.ref048","doi-asserted-by":"crossref","first-page":"7189","DOI":"10.1074\/jbc.M116.774471","article-title":"Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements","volume":"292","author":"SA Mookerjee","year":"2017","journal-title":"J Biol Chem"},{"key":"pcbi.1012959.ref049","doi-asserted-by":"crossref","first-page":"110841","DOI":"10.1016\/j.exger.2020.110841","article-title":"Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan","volume":"132","author":"R Castro-Portuguez","year":"2020","journal-title":"Exp Gerontol"},{"key":"pcbi.1012959.ref050","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.biocel.2014.02.003","article-title":"Effect of Coenzyme Q10 supplementation on mitochondrial electron transport chain activity and mitochondrial oxidative stress in Coenzyme Q10 deficient human neuronal cells","volume":"50","author":"KE Duberley","year":"2014","journal-title":"Int J Biochem Cell Biol"},{"issue":"1","key":"pcbi.1012959.ref051","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3390\/antiox11010002","article-title":"Coenzyme Q10, Ageing and the Nervous System: An Overview","volume":"11","author":"D Mantle","year":"2021","journal-title":"Antioxidants (Basel)"},{"issue":"12","key":"pcbi.1012959.ref052","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1016\/j.freeradbiomed.2004.08.021","article-title":"Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures","volume":"37","author":"M Patel","year":"2004","journal-title":"Free Radic Biol Med"},{"key":"pcbi.1012959.ref053","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3389\/fncel.2018.00335","article-title":"Bioenergetic Mechanisms of Seizure Control","volume":"12","author":"R Kov\u00e1cs","year":"2018","journal-title":"Front Cell Neurosci"},{"key":"pcbi.1012959.ref054","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.yebeh.2018.09.007","article-title":"Afterdischarges elicited by cortical electric stimulation in humans: When do they occur and what do they mean?","volume":"87","author":"S Gollwitzer","year":"2018","journal-title":"Epilepsy Behav"},{"key":"pcbi.1012959.ref055","doi-asserted-by":"crossref","first-page":"1441297","DOI":"10.3389\/fsci.2025.1441297","article-title":"Breakdown and repair of metabolism in the aging brain","volume":"3","author":"P Shichkova","year":"2025","journal-title":"Frontiers in Science"},{"issue":"5134","key":"pcbi.1012959.ref056","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.7901908","article-title":"Oxidative stress, glutamate, and neurodegenerative disorders","volume":"262","author":"JT Coyle","year":"1993","journal-title":"Science"},{"issue":"3","key":"pcbi.1012959.ref057","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1073\/pnas.96.3.846","article-title":"Mitochondrial disease in superoxide dismutase 2 mutant mice","volume":"96","author":"S Melov","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pcbi.1012959.ref058","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1113\/jphysiol.2003.042416","article-title":"Glycogen Regulation and Functional Role in Mouse White Matter","volume":"549","author":"AM Brown","year":"2003","journal-title":"The Journal of Physiology"},{"issue":"48","key":"pcbi.1012959.ref059","doi-asserted-by":"crossref","first-page":"20602","DOI":"10.1073\/pnas.1013798107","article-title":"Imbalance of ionic conductances contributes to diverse symptoms of demyelination","volume":"107","author":"JS Coggan","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1012959.ref060","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fncom.2017.00025","article-title":"Understanding Epileptiform After-Discharges as Rhythmic Oscillatory Transients","volume":"11","author":"G Baier","year":"2017","journal-title":"Front Comput Neurosci"},{"issue":"1","key":"pcbi.1012959.ref061","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3988\/jcn.2015.11.1.26","article-title":"Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: a meta-analysis","volume":"11","author":"F Ye","year":"2015","journal-title":"J Clin Neurol"},{"issue":"Pt B","key":"pcbi.1012959.ref062","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.neuroimage.2016.04.049","article-title":"The Virtual Epileptic Patient: Individualized whole-brain models of epilepsy spread","volume":"145","author":"VK Jirsa","year":"2017","journal-title":"Neuroimage"},{"key":"pcbi.1012959.ref063","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.brainresbull.2018.12.021","article-title":"ATP release during seizures - A critical evaluation of the evidence","volume":"151","author":"E Beamer","year":"2019","journal-title":"Brain Res Bull"},{"key":"pcbi.1012959.ref064","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3389\/fnut.2018.00075","article-title":"Ketogenic Ratio Determines Metabolic Effects of Macronutrients and Prevents Interpretive Bias","volume":"5","author":"T Zilberter","year":"2018","journal-title":"Front Nutr"},{"key":"pcbi.1012959.ref065","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.yebeh.2014.08.015","article-title":"Does ketogenic diet improve cognitive function in patients with GLUT1-DS? A 6- to 17-month follow-up study","volume":"39","author":"A Ramm-Pettersen","year":"2014","journal-title":"Epilepsy Behav"},{"issue":"2","key":"pcbi.1012959.ref066","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/jimd.12175","article-title":"Glucose transporter type 1 deficiency syndrome and the ketogenic diet","volume":"43","author":"M Schwantje","year":"2020","journal-title":"J Inherit Metab Dis"},{"key":"pcbi.1012959.ref067","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ejpn.2023.05.005","article-title":"Uncommon use of intermittent glucose administration for infrequent non-epileptic paroxysmal events in GLUT1-DS","volume":"45","author":"S Mortaji","year":"2023","journal-title":"Eur J Paediatr Neurol"},{"key":"pcbi.1012959.ref068","doi-asserted-by":"crossref","first-page":"846183","DOI":"10.3389\/fnhum.2022.846183","article-title":"Exogenous Ketones and Lactate as a Potential Therapeutic Intervention for Brain Injury and Neurodegenerative Conditions","volume":"16","author":"NE Omori","year":"2022","journal-title":"Front Hum Neurosci"},{"issue":"6","key":"pcbi.1012959.ref069","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1038\/s41380-022-01521-x","article-title":"Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability","volume":"29","author":"H Zhang","year":"2024","journal-title":"Mol Psychiatry"},{"issue":"10","key":"pcbi.1012959.ref070","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1097\/00004647-200010000-00012","article-title":"Human brain beta-hydroxybutyrate and lactate increase in fasting-induced ketosis","volume":"20","author":"JW Pan","year":"2000","journal-title":"J Cereb Blood Flow Metab"},{"issue":"13","key":"pcbi.1012959.ref071","doi-asserted-by":"crossref","first-page":"4768","DOI":"10.1523\/JNEUROSCI.6612-10.2011","article-title":"Lactate transport and metabolism in the human brain: implications for the astrocyte-neuron lactate shuttle hypothesis","volume":"31","author":"CR Figley","year":"2011","journal-title":"J Neurosci"},{"issue":"42","key":"pcbi.1012959.ref072","doi-asserted-by":"crossref","first-page":"13983","DOI":"10.1523\/JNEUROSCI.2040-10.2010","article-title":"The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy","volume":"30","author":"F Boumezbeur","year":"2010","journal-title":"J Neurosci"},{"issue":"3","key":"pcbi.1012959.ref073","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1113\/JP274945","article-title":"CrossTalk opposing view: lack of evidence supporting an astrocyte-to-neuron lactate shuttle coupling neuronal activity to glucose utilisation in the brain","volume":"596","author":"LK Bak","year":"2018","journal-title":"J Physiol"},{"issue":"7","key":"pcbi.1012959.ref074","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/jcbfm.2011.149","article-title":"Sweet sixteen for ANLS","volume":"32","author":"L Pellerin","year":"2012","journal-title":"J Cereb Blood Flow Metab"},{"issue":"5","key":"pcbi.1012959.ref075","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.cell.2011.02.018","article-title":"Astrocyte-neuron lactate transport is required for long-term memory formation","volume":"144","author":"A Suzuki","year":"2011","journal-title":"Cell"},{"key":"pcbi.1012959.ref076","doi-asserted-by":"crossref","first-page":"807970","DOI":"10.3389\/fnut.2021.807970","article-title":"Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer\u2019s Disease: A Mini Review","volume":"8","author":"M Lilamand","year":"2022","journal-title":"Front Nutr"},{"issue":"6","key":"pcbi.1012959.ref077","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1007\/s00431-022-04446-3","article-title":"Lactate infusion as therapeutical intervention: a scoping review","volume":"181","author":"LA van Gemert","year":"2022","journal-title":"Eur J Pediatr"},{"key":"pcbi.1012959.ref078","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3389\/fnmol.2017.00377","article-title":"Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?","volume":"10","author":"M Elamin","year":"2017","journal-title":"Front Mol Neurosci"},{"issue":"1","key":"pcbi.1012959.ref079","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s11064-020-02964-w","article-title":"Aerobic Glycolysis in the Brain: Warburg and Crabtree Contra Pasteur","volume":"46","author":"LF Barros","year":"2021","journal-title":"Neurochem Res"},{"key":"pcbi.1012959.ref080","doi-asserted-by":"crossref","first-page":"112335","DOI":"10.1016\/j.celrep.2023.112335","article-title":"Neurons require glucose uptake and glycolysis in vivo","volume":"42","author":"H Li","year":"2023","journal-title":"Cell Reports"},{"key":"pcbi.1012959.ref081","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3389\/fnene.2011.00008","article-title":"Carbohydrate-biased control of energy metabolism: the darker side of the selfish brain","volume":"3","author":"T Zilberter","year":"2011","journal-title":"Front Neuroenergetics"},{"issue":"1","key":"pcbi.1012959.ref082","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/j.2040-1124.2010.00070.x","article-title":"Mechanism of diabetic neuropathy: Where are we now and where to go?","volume":"2","author":"S Yagihashi","year":"2011","journal-title":"J Diabetes Investig"},{"issue":"11","key":"pcbi.1012959.ref083","first-page":"1061","article-title":"Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer\u2019s disease","volume":"32","author":"GE Gibson","year":"2002","journal-title":"Free Radic Biol Med"},{"key":"pcbi.1012959.ref084","doi-asserted-by":"crossref","first-page":"825816","DOI":"10.3389\/fphys.2021.825816","article-title":"Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives","volume":"12","author":"E Beard","year":"2022","journal-title":"Front Physiol"},{"issue":"2","key":"pcbi.1012959.ref085","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1042\/bst0210549","article-title":"Mechanism for the formation of methylglyoxal from triosephosphates","volume":"21","author":"JP Richard","year":"1993","journal-title":"Biochem Soc Trans"},{"issue":"1","key":"pcbi.1012959.ref086","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0006-8993(02)02877-9","article-title":"Nitric oxide accounts for an increased glycolytic rate in activated astrocytes through a glycogenolysis-independent mechanism","volume":"945","author":"A Almeida","year":"2002","journal-title":"Brain Res"},{"key":"pcbi.1012959.ref087","doi-asserted-by":"crossref","first-page":"e67659","DOI":"10.7554\/eLife.67659","article-title":"High and stable ATP levels prevent aberrant intracellular protein aggregation in yeast","volume":"11","author":"M Takaine","year":"2022","journal-title":"Elife"},{"issue":"6339","key":"pcbi.1012959.ref088","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1126\/science.aaf6846","article-title":"ATP as a biological hydrotrope","volume":"356","author":"A Patel","year":"2017","journal-title":"Science"},{"issue":"3","key":"pcbi.1012959.ref089","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.cmet.2018.11.005","article-title":"Non-Canonical Control of Neuronal Energy Status by the Na+ Pump","volume":"29","author":"F Baeza-Lehnert","year":"2019","journal-title":"Cell Metab"},{"issue":"5","key":"pcbi.1012959.ref090","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.neuron.2012.08.019","article-title":"Synaptic energy use and supply","volume":"75","author":"JJ Harris","year":"2012","journal-title":"Neuron"},{"issue":"9","key":"pcbi.1012959.ref091","doi-asserted-by":"crossref","first-page":"e1011464","DOI":"10.1371\/journal.pcbi.1011464","article-title":"Mechanistic multiscale modelling of energy metabolism in human astrocytes reveals the impact of morphology changes in Alzheimer\u2019s Disease","volume":"19","author":"S Farina","year":"2023","journal-title":"PLoS Comput Biol"},{"issue":"9","key":"pcbi.1012959.ref092","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1002\/glia.20990","article-title":"The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction","volume":"58","author":"TM Mathiisen","year":"2010","journal-title":"Glia"},{"key":"pcbi.1012959.ref093","doi-asserted-by":"crossref","first-page":"800901","DOI":"10.3389\/fnut.2022.800901","article-title":"Lactate Is Answerable for Brain Function and Treating Brain Diseases: Energy Substrates and Signal Molecule","volume":"9","author":"M Cai","year":"2022","journal-title":"Front Nutr"},{"issue":"22","key":"pcbi.1012959.ref094","doi-asserted-by":"crossref","first-page":"8767","DOI":"10.3390\/ijms21228767","article-title":"Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases","volume":"21","author":"NJ Jensen","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"9","key":"pcbi.1012959.ref095","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1038\/jcbfm.2015.70","article-title":"Physiology-based kinetic modeling of neuronal energy metabolism unravels the molecular basis of NAD(P)H fluorescence transients","volume":"35","author":"N Berndt","year":"2015","journal-title":"J Cereb Blood Flow Metab"},{"issue":"2","key":"pcbi.1012959.ref096","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1177\/0271678X17693024","article-title":"Mathematical analysis of the influence of brain metabolism on the BOLD signal in Alzheimer\u2019s disease","volume":"38","author":"F Winter","year":"2018","journal-title":"J Cereb Blood Flow Metab"},{"issue":"3","key":"pcbi.1012959.ref097","doi-asserted-by":"crossref","first-page":"e12924","DOI":"10.1111\/acel.12924","article-title":"Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer\u2019s disease neurons","volume":"18","author":"P Theurey","year":"2019","journal-title":"Aging Cell"},{"key":"pcbi.1012959.ref098","doi-asserted-by":"crossref","first-page":"111090","DOI":"10.1016\/j.jtbi.2022.111090","article-title":"Representing stimulus information in an energy metabolism pathway","volume":"540","author":"JS Coggan","year":"2022","journal-title":"J Theor Biol"},{"key":"pcbi.1012959.ref099","article-title":"Julia: A Fresh Approach to Numerical Computing","author":"J Bezanson","year":"2014","journal-title":"arXiv"},{"issue":"5","key":"pcbi.1012959.ref100","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1203\/PDR.0b013e318184d2b5","article-title":"Functional studies of the T295M mutation causing Glut1 deficiency: glucose efflux preferentially affected by T295M","volume":"64","author":"D Wang","year":"2008","journal-title":"Pediatr Res"},{"key":"pcbi.1012959.ref101","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/B978-0-12-398397-8.00005-8","article-title":"Carbohydrate intake","volume":"108","author":"A Leturque","year":"2012","journal-title":"Prog Mol Biol Transl Sci"},{"key":"pcbi.1012959.ref102","doi-asserted-by":"crossref","first-page":"1103026","DOI":"10.3389\/fneur.2023.1103026","article-title":"Correlation between blood glucose and cerebrospinal fluid glucose levels in patients with differences in glucose metabolism","volume":"14","author":"QC Tan","year":"2023","journal-title":"Front Neurol"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1012959","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012959","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T17:57:13Z","timestamp":1744826233000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012959"}},"subtitle":[],"editor":[{"given":"Renaud Blaise","family":"Jolivet","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,4,4]]},"references-count":102,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1012959","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1012959","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,4]]}}}