{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T03:27:38Z","timestamp":1787110058337,"version":"build-2736575974"},"reference-count":67,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J of Neuroscience"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Cerebral ischemia impairs neuronal and glial function, ranging from transient synaptic failure to irreversible damage. The effects of ischemia on excitatory synaptic transmission remain incompletely understood. Here, we present a detailed biophysical model, including the first full implementation of the glutamate\u2013glutamine cycle (GG\u2010cycle), which is essential for proper functioning of glutamatergic synapses. We model a presynaptic neuron and an astrocyte in a finite extracellular space (ECS), surrounded by an oxygen bath as a proxy for energy supply. The model includes ionic currents with corresponding channels and transporters such as the sodium\u2010potassium ATPase. To model synaptic transmission, we combine calcium\u2010dependent glutamate release, its uptake by the sodium\u2010dependent excitatory amino acid transporters (EAATs), and the GG\u2010cycle, including glutamine synthesis. We simulate ischemia by blocking energy supply completely. This drives the neuron into depolarization block, with pathological ion concentrations and extracellular glutamate accumulation despite disrupted synaptic release. Synaptic transmission failure is not primarily caused by excessive glutamate release or by failure of glutamine synthetase, but mainly results from EAAT dysfunction, driven by the collapse of the sodium gradient. Restoring synaptic transmission is not possible by solely targeting glutamate dynamics but is possible by restoring ion gradients by inhibition of the voltage\u2010gated Na\n                    <jats:sup>+<\/jats:sup>\n                    \u2010channel. Our study highlights the critical role of ion homeostasis, in particular the sodium gradient, in failure and recovery of synaptic function and the EAAT during metabolic stress.\n                  <\/jats:p>","DOI":"10.1111\/ejn.70604","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T07:13:47Z","timestamp":1783667627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of the Glutamate\u2013Glutamine Cycle in Synaptic Transmission During Ischemia and Recovery"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7536-4677","authenticated-orcid":false,"given":"Hannah","family":"van Susteren","sequence":"first","affiliation":[{"name":"Department of Applied Mathematics University of Twente  Enschede the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9684-3592","authenticated-orcid":false,"given":"Christine R.","family":"Rose","sequence":"additional","affiliation":[{"name":"Institute of Neurobiology Heinrich Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8319-3626","authenticated-orcid":false,"given":"Michel J. A. M.","family":"van Putten","sequence":"additional","affiliation":[{"name":"Clinical Neurophysiology Group, Department of Science and Technology University of Twente  Enschede the Netherlands"},{"name":"Medisch Spectrum Twente  Enschede the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1526-3762","authenticated-orcid":false,"given":"Hil G. E.","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Applied Mathematics University of Twente  Enschede the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncom.2012.00070"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.03913.x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4201"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1984.tb05396.x"},{"key":"e_1_2_11_6_1","unstructured":"Berl S. andD. D.Clarke.1983. \u201cThe Metabolic Compartmentation Concept.\u201d Chemistry Faculty Publications."},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2012.139"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006151"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.013303"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00322.x"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10011"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200201070"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81674-8"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7254.2006.00399.x"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(88)90162-6"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.12.062"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12232675"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006040"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2016.04.004"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23995"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.98"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00585346"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.111.632943"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005804"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0148110"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1009019"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20817"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(84)80610-0"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj0291951"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007668801570"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10041"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1665-2681(19)31785-5"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00156.x"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-003-1117-9"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212718200"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8020184"},{"key":"e_1_2_11_37_1","first-page":"193","article-title":"Excitotoxicity: An Organized Crime at the Cellular Level","volume":"8","author":"Martinez Cruz M.","year":"2017","journal-title":"Journal of Neurology and Neuroscience"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.10-01-00283.1990"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1992.tb09788.x"},{"key":"e_1_2_11_40_1","doi-asserted-by":"crossref","unstructured":"Nicoli A. L. A. S.Al Abed S. R.Hulme et\u00a0al.2024. \u201cGlutamine Transport via Neurotransmitter Transporter 4 (NTT4 SLC6A17) Maintains Presynaptic Glutamate Supply at Excitatory Synapses in the Central Nervous System.\u201d bioRxiv 2024.10.20.616835.","DOI":"10.1101\/2024.10.20.616835"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881118754680"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-199901000-00001"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.637784"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(92)90639-Q"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00451"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/35002090"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1984.tb05406.x"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1385\/MN:24:1-3:107"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-08894-5_2"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnene.2013.00001"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.95.5.837"},{"issue":"2010","key":"e_1_2_11_52_1","first-page":"1239","article-title":"SAT1, a Glutamine Transporter, Is Preferentially Expressed in GABAergic Neurons","volume":"4","author":"Solbu T. T.","year":"2010","journal-title":"Frontiers in Neuroanatomy"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.12.026"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23133"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.2.719"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.23.2.253"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2011.226605"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115679"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1986.tb12973.x"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2005.04.012"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0750471.x"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1994.63031003.x"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003362"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0516-14.2014"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-008-9121-8"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002965200"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199810050-00011"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2025.112256"}],"container-title":["European Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejn.70604","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ejn.70604","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejn.70604","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T02:49:23Z","timestamp":1787107763000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ejn.70604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":67,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1111\/ejn.70604"],"URL":"https:\/\/doi.org\/10.1111\/ejn.70604","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/EJN.70604\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/EJN.70604\/v1\/review3","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/EJN.70604\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/EJN.70604\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/EJN.70604\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/EJN.70604\/v1\/review1","asserted-by":"object"}]},"ISSN":["0953-816X","1460-9568"],"issn-type":[{"value":"0953-816X","type":"print"},{"value":"1460-9568","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]},"assertion":[{"value":"2025-11-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70604"}}