title: Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia.
abstract: 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-beta-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.
authors.affiliation: Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Campbell
authors.forename: John J
authors.initials: JJ
authors.lastname: Hablitz
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000494:pharmacology; D002540:Cerebral Cortex / Q000473:pathology*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D054220:Malformations of Cortical Development / Q000209:etiology / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D027322:Amino Acid Transport System X-AG; D018691:Excitatory Amino Acid Antagonists; C120673:benzyloxyaspartate; D001224:Aspartic Acid; C020889:dihydrokainic acid; D015763:2-Amino-5-phosphonovalerate; D007608:Kainic Acid