Prolonged activation of the N-methyl-D-aspartate receptor-Ca2+ transduction pathway causes spontaneous recurrent epileptiform discharges in hippocampal neurons in culture.
The molecular basis for developing symptomatic epilepsy (epileptogenesis) remains ill defined. We show here in a well characterized hippocampal culture model of epilepsy that the induction of epileptogenesis is Ca2+-dependent. The concentration of intracellular free Ca2+ ([Ca2+]i) was monitored during the induction of epileptogenesis by prolonged electrographic seizure activity induced through low-Mg2+ treatment by confocal laser-scanning fluorescent microscopy to directly correlate changes in [Ca2+]i with alterations in membrane excitability measured by intracellular recording using whole-cell current-clamp techniques. The induction of long-lasting spontaneous recurrent epileptiform discharges, but not the Mg2+-induced spike discharges, was prevented in low-Ca2+ solutions and was dependent on activation of the N-methyl-D-aspartate (NMDA) receptor. The results provide direct evidence that prolonged activation of the NMDA-Ca2+ transduction pathway causes a long-lasting plasticity change in hippocampal neurons causing increased excitability leading to the occurrence of spontaneous, recurrent epileptiform discharges.
DeLorenzo
R J
RJ
Department of Neurology, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA 23298, USA. rdeloren@hsc.vcu.edu
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Sombati
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001565:Benzoates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004827:Epilepsy / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology*; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C079694:alpha-methyl-4-carboxyphenylglycine; D004533:Egtazic Acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D008274:Magnesium; D009543:Nifedipine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; D005998:Glycine