Potassium and glutamate transport is impaired in scar-forming tumor-associated astrocytes

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dc.contributor.authorCampbell, Susan C.en
dc.contributor.authorMuñoz-Ballester, Carmenen
dc.contributor.authorChaunsali, Lataen
dc.contributor.authorMills, William A.en
dc.contributor.authorYang, Jennifer H.en
dc.contributor.authorSontheimer, Haralden
dc.contributor.authorRobel, Stefanieen
dc.contributor.departmentAnimal and Poultry Sciencesen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentSchool of Neuroscienceen
dc.date.accessioned2020-01-20T20:48:45Zen
dc.date.available2020-01-20T20:48:45Zen
dc.date.issued2019-12-09en
dc.date.updated2020-01-20T20:48:41Zen
dc.description.abstractUnprovoked recurrent seizures are a serious comorbidity affecting most patients who suffer from glioma, a primary brain tumor composed of malignant glial cells. Cellular mechanisms contributing to the development of recurrent spontaneous seizures include the release of the excitatory neurotransmitter glutamate from glioma into extracellular space. Under physiological conditions, astrocytes express two high affinity glutamate transporters, Glt-1 and Glast, which are responsible for the removal of excess extracellular glutamate. In the context of neurological disease or brain injury, astrocytes become reactive which can negatively affect neuronal function, causing hyperexcitability and/or death. Using electrophysiology, immunohistochemistry, fluorescent in situ hybridization, and Western blot analysis in different orthotopic xenograft and allograft models of human and mouse gliomas, we find that peritumoral astrocytes exhibit astrocyte scar formation characterized by proliferation, cellular hypertrophy, process elongation, and increased GFAP and pSTAT3. Overall, peritumoral reactive astrocytes show a significant reduction in glutamate and potassium uptake, as well as decreased glutamine synthetase activity. A subset of peritumoral astrocytes displayed a depolarized resting membrane potential, further contributing to reduced potassium and glutamate homeostasis. These changes may contribute to the propagation of peritumoral neuronal hyperexcitability and excitotoxic death.en
dc.description.sponsorshipFunding was provided by the National Institutes of Health (NIH) RO1 NS036692 (HS), RO1 NS082851 (HS), RO1 NS052634 (HS), RO1 NS105807 (SR). SR was also supported by the Epilepsy Foundation and the American Brain Tumor Association (ABTA).en
dc.description.versionAccepted versionen
dc.format.extentPages 104628en
dc.format.mimetypeapplication/pdfen
dc.identifier104628 (Article number)en
dc.identifier.doihttps://doi.org/10.1016/j.neuint.2019.104628en
dc.identifier.eissn1872-9754en
dc.identifier.issn0197-0186en
dc.identifier.orcidRobel, Stefanie [0000-0001-6716-3670]en
dc.identifier.orcidSontheimer, Harald [0000-0002-5843-9871]en
dc.identifier.orcidCampbell, Susan [0000-0001-7775-8600]en
dc.identifier.otherS0197-0186(19)30363-8 (PII)en
dc.identifier.pmid31825815en
dc.identifier.urihttp://hdl.handle.net/10919/96513en
dc.identifier.volume133en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/31825815en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectAcquired epilepsyen
dc.subjectAstrogliosisen
dc.subjectGlial scaren
dc.subjectReactive astrocytesen
dc.subjectSeizuresen
dc.subjectTumor-associated epilepsyen
dc.subject1101 Medical Biochemistry and Metabolomicsen
dc.subject1109 Neurosciencesen
dc.subjectNeurology & Neurosurgeryen
dc.titlePotassium and glutamate transport is impaired in scar-forming tumor-associated astrocytesen
dc.title.serialNeurochemistry Internationalen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherJournal Articleen
dcterms.dateAccepted2019-12-05en
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutes/Virginia Tech Carilion Research Instituteen
pubs.organisational-group/Virginia Tech/Science/Dual appointment facultyen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen
pubs.organisational-group/Virginia Tech/Science/School of Neuroscienceen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Durelle Scotten
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Animal and Poultry Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen

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