{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:16:01Z","timestamp":1790223361432,"version":"4.1.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T00:00:00Z","timestamp":1611792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003121","name":"Ferdowsi University of Mashhad","doi-asserted-by":"publisher","award":["3\/44083"],"award-info":[{"award-number":["3\/44083"]}],"id":[{"id":"10.13039\/501100003121","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>It is known that hippocampal epileptogenesis is accompanied by hyperexcitability, glutamate-related neuronal dysfunctions and consequently cognitive deficits. However, the neuroprotective role of astrocytic glutamate uptake through the Glutamate Transporter-1 (GLT-1) remains to be unknown in these processes. Therefore, to assess the effect of glutamate uptake, pharmacological upregulation of GLT-1 using ceftriaxone administration (200 mg\/kg\/day, i.p, 5 days) was utilized in Li-PIL animal models of temporal lobe epilepsy (TLE). Glutamate concentration and glutamine synthetase activity were analyzed using biochemical assays. In addition, GLT-1 gene expression was assessed by RT-qPCR. Finally, cognitive function was studied using Morris water maze (MWM) test and novel object recognition task (NORT). Our results demonstrated that the acute phase of epileptogenesis (first 72 hours after Status Epilepticus) was accompanied by an increase in the hippocampal glutamate and downregulation of GLT-1 mRNA expression compared to controls. Ceftriaxone administration in epileptic animals led to a reduction of glutamate along with elevation of the level of glutamine synthetase activity and GLT-1 expression in the acute phase. In the chronic phase of epileptogenesis (4 weeks after Status Epilepticus), glutamate levels and GLT-1 expression were decreased compared to controls. Ceftriaxone treatment increased the levels of GLT-1 expression. Furthermore, impaired learning and memory ability in the chronic phase of epileptogenesis was rescued by Ceftriaxone administration. This study shows that astrocytic glutamate uptake can profoundly impact the processes of hippocampal epileptogenesis through the reduction of glutamate-induced excitotoxicity and consequently rescuing of cognitive deficits caused by epilepsy.<\/jats:p>","DOI":"10.1371\/journal.pone.0246068","type":"journal-article","created":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T19:00:41Z","timestamp":1611860441000},"page":"e0246068","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":30,"title":["Pharmacological upregulation of GLT-1 alleviates the cognitive impairments in the animal model of temporal lobe epilepsy"],"prefix":"10.1371","volume":"16","author":[{"given":"Daniel","family":"Ramandi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Elahdadi Salmani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Moghimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taghi","family":"Lashkarbolouki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5250-898X","authenticated-orcid":true,"given":"Masoud","family":"Fereidoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,28]]},"reference":[{"issue":"6","key":"pone.0246068.ref001","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a022426","article-title":"Seizures and epilepsy: an overview for neuroscientists","volume":"5","author":"CE Stafstrom","year":"2015","journal-title":"Cold Spring Harbor perspectives in medicine"},{"issue":"10","key":"pone.0246068.ref002","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1007\/s12098-014-1530-4","article-title":"Epilepsy, cognition and behavior","volume":"81","author":"S Gulati","year":"2014","journal-title":"Indian journal of pediatrics"},{"issue":"6","key":"pone.0246068.ref003","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/j.bbadis.2017.02.003","article-title":"Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy","volume":"1863","author":"BL Clossen","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"issue":"Spec No 1","key":"pone.0246068.ref004","first-page":"S6","article-title":"What are the effects of prolonged seizures in the brain?","volume":"16","author":"RC Scott","year":"2014","journal-title":"Epileptic disorders: international epilepsy journal with videotape"},{"issue":"7","key":"pone.0246068.ref005","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.neuint.2013.01.017","article-title":"Glial cell changes in epilepsy: overview of the clinical problem and therapeutic opportunities","volume":"63","author":"JA Hubbard","year":"2013","journal-title":"Neurochemistry international"},{"key":"pone.0246068.ref006","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/B978-0-12-420170-5.00003-9","article-title":"CaMKII: a molecular substrate for synaptic plasticity and memory","volume":"122","author":"BC Shonesy","year":"2014","journal-title":"Prog Mol Biol Transl Sci"},{"issue":"2","key":"pone.0246068.ref007","doi-asserted-by":"crossref","first-page":"75","DOI":"10.2220\/biomedres.34.75","article-title":"Synaptic plasticity in hippocampal CA1 neurons and learning behavior in transient ischemia-loaded gerbils","volume":"34","author":"J Li","year":"2013","journal-title":"Biomed Res"},{"issue":"5","key":"pone.0246068.ref008","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1523\/JNEUROSCI.2774-16.2016","article-title":"Pharmacological Rescue of Long-Term Potentiation in Alzheimer Diseased Synapses","volume":"37","author":"GA Prieto","year":"2017","journal-title":"The Journal of neuroscience: the official journal of the Society for Neuroscience"},{"key":"pone.0246068.ref009","doi-asserted-by":"crossref","DOI":"10.1155\/2017\/8087401","article-title":"Functional Metaplasticity of Hippocampal Schaffer Collateral-CA1 Synapses Is Reversed in Chronically Epileptic Rats","volume":"2017","author":"M Rehberg","year":"2017","journal-title":"Neural Plast"},{"key":"pone.0246068.ref010","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3389\/fncel.2013.00159","article-title":"How do astrocytes shape synaptic transmission? 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