Abstract
Using microcultured neurons and hippocampal slices, we found that under conditions that completely block AMPA receptors, kainate induces a reduction in the effectiveness of GABAergic synaptic inhibition. Evoked inhibitory postsynaptic currents (IPSCs) were decreased by kainate by up to 90%, showing a bell-shaped dose-response curve similar to that of native kainate-selective receptors. The down-regulation of GABAergic inhibition was not affected by antagonism of metabotropic receptors, while it was attenuated by CNQX. Kainate increased synaptic failures and reduced the frequency of miniature IPSCs, indicating a presynaptic locus of action. In vivo experiments using brain dialysis demonstrated that kainate reversibly abolished recurrent inhibition and induced an epileptic-like electroencephalogram (EEG) activity. These results indicate that kainate receptor activation down-regulates GABAergic inhibition by modulating the reliability of GABA synapses.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
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Animals
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Bicuculline / pharmacology
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Cells, Cultured
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Electric Stimulation
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Electroencephalography / drug effects
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Embryo, Mammalian
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Epilepsy
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Evoked Potentials / drug effects
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Evoked Potentials / physiology
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Female
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Functional Laterality
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GABA Antagonists / pharmacology*
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Hippocampus / physiology*
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In Vitro Techniques
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Kainic Acid / pharmacology*
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Neurons / physiology*
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Pyramidal Cells / physiology
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Receptors, Kainic Acid / physiology*
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Receptors, Presynaptic / physiology*
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
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Tetrodotoxin / pharmacology
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gamma-Aminobutyric Acid / physiology*
Substances
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GABA Antagonists
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Receptors, Kainic Acid
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Receptors, Presynaptic
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Tetrodotoxin
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gamma-Aminobutyric Acid
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6-Cyano-7-nitroquinoxaline-2,3-dione
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2-Amino-5-phosphonovalerate
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Kainic Acid
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Bicuculline