Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia
Glutamate transporters function to maintain low levels of extracellular glutamate and play an important role in synaptic transmission at many synapses. Disruption of glutamate transporter function or expression can result in increased extracellular glutamate levels. Alterations in glutamate transpor...
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doaj-7ae843a6ebe44143990574d77317d2d82021-03-20T04:56:10ZengElsevierNeurobiology of Disease1095-953X2008-11-01322254261Decreased glutamate transport enhances excitability in a rat model of cortical dysplasiaSusan L. Campbell0John J. Hablitz1Department of Neurobiology and Center for Glial Biology in Medicine University of Alabama at Birmingham, Birmingham, AL 35294, USACorresponding author. Fax: +1 205 934 6571.; Department of Neurobiology and Center for Glial Biology in Medicine University of Alabama at Birmingham, Birmingham, AL 35294, USAGlutamate transporters function to maintain low levels of extracellular glutamate and play an important role in synaptic transmission at many synapses. Disruption of glutamate transporter function or expression can result in increased extracellular glutamate levels. Alterations in glutamate transporter expression have been reported in human epilepsy and animal seizure models. Functional electrophysiological changes that occur when transporter expression is disrupted in chronic epilepsy models have not been examined. Here, we used a freeze-induced model of cortical dysplasia to test the role of glutamate transporters in synaptic hyperexcitability. We report that inhibiting glutamate transporters with the non-selective antagonist, dl-threo-β-benzylozyaspartic acid (TBOA) preferentially prolongs postsynaptic currents (PSCs) and decreases the threshold for evoking epileptiform activity in lesioned compared to control cortex. The effect of inhibiting uptake is mediated primarily by the glia glutamate transporter (GLT-1) since the selective antagonist dihydrokainate (DHK) mimicked the effects of TBOA. The effect of uptake inhibition is mediated by activation of N-methyl-d-aspartate (NMDA) receptors since d-(−)-2-amino-5-phosphonovaleric acid (APV) prevents TBOA-induced effects. Neurons in lesioned cortex also have a larger tonic NMDA current. These results indicate that chronic changes in glutamate transporters and NMDA receptors contribute to hyperexcitability in cortical dysplasia.http://www.sciencedirect.com/science/article/pii/S0969996108001599NeocortexCortical dysplasiaGlutamate transportersTBOAGLT-1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Susan L. Campbell John J. Hablitz |
spellingShingle |
Susan L. Campbell John J. Hablitz Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia Neurobiology of Disease Neocortex Cortical dysplasia Glutamate transporters TBOA GLT-1 |
author_facet |
Susan L. Campbell John J. Hablitz |
author_sort |
Susan L. Campbell |
title |
Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia |
title_short |
Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia |
title_full |
Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia |
title_fullStr |
Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia |
title_full_unstemmed |
Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia |
title_sort |
decreased glutamate transport enhances excitability in a rat model of cortical dysplasia |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2008-11-01 |
description |
Glutamate transporters function to maintain low levels of extracellular glutamate and play an important role in synaptic transmission at many synapses. Disruption of glutamate transporter function or expression can result in increased extracellular glutamate levels. Alterations in glutamate transporter expression have been reported in human epilepsy and animal seizure models. Functional electrophysiological changes that occur when transporter expression is disrupted in chronic epilepsy models have not been examined. Here, we used a freeze-induced model of cortical dysplasia to test the role of glutamate transporters in synaptic hyperexcitability. We report that inhibiting glutamate transporters with the non-selective antagonist, dl-threo-β-benzylozyaspartic acid (TBOA) preferentially prolongs postsynaptic currents (PSCs) and decreases the threshold for evoking epileptiform activity in lesioned compared to control cortex. The effect of inhibiting uptake is mediated primarily by the glia glutamate transporter (GLT-1) since the selective antagonist dihydrokainate (DHK) mimicked the effects of TBOA. The effect of uptake inhibition is mediated by activation of N-methyl-d-aspartate (NMDA) receptors since d-(−)-2-amino-5-phosphonovaleric acid (APV) prevents TBOA-induced effects. Neurons in lesioned cortex also have a larger tonic NMDA current. These results indicate that chronic changes in glutamate transporters and NMDA receptors contribute to hyperexcitability in cortical dysplasia. |
topic |
Neocortex Cortical dysplasia Glutamate transporters TBOA GLT-1 |
url |
http://www.sciencedirect.com/science/article/pii/S0969996108001599 |
work_keys_str_mv |
AT susanlcampbell decreasedglutamatetransportenhancesexcitabilityinaratmodelofcorticaldysplasia AT johnjhablitz decreasedglutamatetransportenhancesexcitabilityinaratmodelofcorticaldysplasia |
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