Dysregulation of Ambient Glutamate and Glutamate Receptors in Epilepsy: An Astrocytic Perspective

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dc.contributor.authorAlcoreza, Oscar Jr.en
dc.contributor.authorPatel, Dipan C.en
dc.contributor.authorTewari, Bhanu P.en
dc.contributor.authorSontheimer, Haralden
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentVirginia Tech Carilion School of Medicineen
dc.date.accessioned2021-04-21T17:16:00Zen
dc.date.available2021-04-21T17:16:00Zen
dc.date.issued2021-03-22en
dc.description.abstractGiven the important functions that glutamate serves in excitatory neurotransmission, understanding the regulation of glutamate in physiological and pathological states is critical to devising novel therapies to treat epilepsy. Exclusive expression of pyruvate carboxylase and glutamine synthetase in astrocytes positions astrocytes as essential regulators of glutamate in the central nervous system (CNS). Additionally, astrocytes can significantly alter the volume of the extracellular space (ECS) in the CNS due to their expression of the bi-directional water channel, aquaporin-4, which are enriched at perivascular endfeet. Rapid ECS shrinkage has been observed following epileptiform activity and can inherently concentrate ions and neurotransmitters including glutamate. This review highlights our emerging knowledge on the various potential contributions of astrocytes to epilepsy, particularly supporting the notion that astrocytes may be involved in seizure initiation via failure of homeostatic responses that lead to increased ambient glutamate. We also review the mechanisms whereby ambient glutamate can influence neuronal excitability, including via generation of the glutamate receptor subunit GluN2B-mediated slow inward currents, as well as indirectly affect neuronal excitability via actions on metabotropic glutamate receptors that can potentiate GluN2B currents and influence neuronal glutamate release probabilities. Additionally, we discuss evidence for upregulation of System xc-, a cystine/glutamate antiporter expressed on astrocytes, in epileptic tissue and changes in expression patterns of glutamate receptors.en
dc.description.notesThis work was supported by NIH grants 1R01CA227149-01A1 and 1R01NS036692-01A1, and DOD grant W81XWH-18-1-0521.en
dc.description.sponsorshipNIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01CA227149-01A1, 1R01NS036692-01A1]; DODUnited States Department of Defense [W81XWH-18-1-0521]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fneur.2021.652159en
dc.identifier.issn1664-2295en
dc.identifier.other652159en
dc.identifier.pmid33828523en
dc.identifier.urihttp://hdl.handle.net/10919/103069en
dc.identifier.volume12en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectglutamate homeostasisen
dc.subjectSystem x(c)(-)en
dc.subjectepilepsyen
dc.subjectastrogliaen
dc.subjectmetabotrophic glutamate receptoren
dc.subjectNMDARen
dc.titleDysregulation of Ambient Glutamate and Glutamate Receptors in Epilepsy: An Astrocytic Perspectiveen
dc.title.serialFrontiers in Neurologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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Scholarly Works, Fralin Biomedical Research Institute at VTC
Destination Area: Adaptive Brain and Behavior (ABB)
Scholarly Works, Virginia Tech Carilion School of Medicine (VTCSOM)