Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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Animals
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Animals, Newborn
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Benzoates / pharmacology
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Calcium / metabolism*
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Calcium / pharmacology
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Cells, Cultured
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Dizocilpine Maleate / pharmacology
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Egtazic Acid / analogs & derivatives
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Egtazic Acid / pharmacology
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Epilepsy / physiopathology*
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Excitatory Amino Acid Antagonists / pharmacology
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Glycine / analogs & derivatives
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Glycine / pharmacology
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Hippocampus / physiology*
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Magnesium / pharmacology
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Microscopy, Confocal
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Neurons / drug effects
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Neurons / physiology*
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Nifedipine / pharmacology
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Patch-Clamp Techniques
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Quinoxalines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate / drug effects
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Receptors, N-Methyl-D-Aspartate / physiology*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
Substances
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Benzoates
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Excitatory Amino Acid Antagonists
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Quinoxalines
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Receptors, N-Methyl-D-Aspartate
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2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
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alpha-methyl-4-carboxyphenylglycine
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Egtazic Acid
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Dizocilpine Maleate
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2-Amino-5-phosphonovalerate
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Magnesium
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Nifedipine
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1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
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Calcium
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Glycine