title: Glutamate uptake shapes low-[Mg2+] induced epileptiform activity in juvenile rat hippocampal slices.
abstract: A wide range of data support a role for ambient glutamate (Glu) in epilepsy, although temporal patterns associated with the cellular uptake of Glu have not been addressed in detail. We report on the effects of Glu uptake inhibitors on recurrent seizure-like events (SLEs) evoked by low-[Mg(2+)] condition in juvenile rat hippocampal slices. Effects were compared for inhibitors such as L-trans-pyrrolidine-2,4-dicarboxylate (tPDC), DL-threo-beta-benzyloxyaspartate (DL-TBOA) and dihydrokainic acid (DHK), representing different transporter specificity and transportability profiles. Latency to the first SLE after drug application was shortened by the inhibitors (in % of control: 500 microM tPDC: 54+/-7, 15 microM DL-TBOA: 74+/-5, 50 microM dl-TBOA: 70+/-6, 100 microM DHK: 69+/-4, 300 microM DHK: 71+/-7). Further SLEs were frequently aborted by higher inhibitor concentrations applied (500 microM tPDC: 2/6, 50 microM TBOA: 5/5, 100 microM DHK: 6/8, 300 microM DHK: 3/3). Simultaneous field potential and whole-cell voltage recordings showed depolarization-induced inactivation of CA3 pyramidal neurons during inhibitor application. In the presence of inhibitors, the amplitude of forthcoming SLE was also decreased (in % of control: 500 microM tPDC: 66+/-9, 15 microM dl-TBOA: 88+/-5, 50 microM dl-TBOA: 59+/-6, 100 microM DHK: 67+/-4, 300 microM DHK: 68+/-1). Dependent on type and concentration of the inhibitor, the duration of the first SLE of drug application either increased (100 microM DHK: 375+/-90 %; 100 microM tPDC: 137+/-13 %) or decreased (50 microM TBOA: 62+/-13 %; 300 microM DHK: 60+/-15 %) reflecting differences in subtype-specificity or mechanism of action of the inhibitors. Our findings suggest a role for ambient Glu in the genesis and maintenance of recurrent epileptiform discharges.
authors.affiliation: Department of Neurochemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri út 59-67, Budapest, Hungary. nyitraig@chemres.hu
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nyitrai
authors.forename: Bálint
authors.initials: B
authors.lastname: Lasztóczi
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008274:Magnesium / Q000378:metabolism*; D008275:Magnesium Deficiency / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D050479:Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D050479:Neurotransmitter Transport Proteins; D011759:Pyrrolidines; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; C020889:dihydrokainic acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D008274:Magnesium; D007608:Kainic Acid