Abstract
Hypoxia is the most common cause of perinatal seizures and can be refractory to conventional anticonvulsant drugs, suggesting an age-specific form of epileptogenesis. A model of hypoxia-induced seizures in immature rats reveals that seizures result in immediate activation of the phosphatase calcineurin (CaN) in area CA1 of hippocampus. After seizures, CA1 pyramidal neurons exhibit a downregulation of GABA(A) receptor (GABA(A)R)-mediated inhibition that was reversed by CaN inhibitors. CaN activation appears to be dependent on seizure-induced activation of Ca2+-permeable AMPA receptors (AMPARs), because the upregulation of CaN activation and GABA(A)R inhibition were attenuated by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] or Joro spider toxin. GABA(A)R beta2/3 subunit protein was dephosphorylated at 1 h after seizures, suggesting this subunit as a possible substrate of CaN in this model. Finally, in vivo administration of the CaN inhibitor FK-506 significantly suppressed hypoxic seizures, and posttreatment with NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline) or FK-506 blocked the hypoxic seizure-induced increase in CaN expression. These data suggest that Ca2+-permeable AMPARs and CaN regulate inhibitory synaptic transmission in a novel plasticity pathway that may play a role in epileptogenesis in the immature brain.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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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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6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
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Animals
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Animals, Newborn
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Blotting, Western / methods
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Calcineurin / physiology*
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Dose-Response Relationship, Radiation
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Electric Stimulation / methods
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Excitatory Postsynaptic Potentials / radiation effects
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / physiology
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Hippocampus* / growth & development
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Hippocampus* / pathology
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Hippocampus* / physiopathology
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Hypoxia / complications
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Immunoprecipitation / methods
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In Vitro Techniques
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Neural Inhibition / drug effects
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Neural Inhibition / physiology
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Neural Inhibition / radiation effects
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Patch-Clamp Techniques / methods
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Rats
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Receptors, AMPA / physiology*
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Receptors, GABA-A / metabolism
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Seizures / etiology
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Seizures / metabolism
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Seizures / physiopathology
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Synapses / metabolism*
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Synaptic Transmission / physiology*
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Tacrolimus / pharmacology
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Time Factors
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gamma-Aminobutyric Acid / metabolism*
Substances
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Excitatory Amino Acid Antagonists
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Receptors, AMPA
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Receptors, GABA-A
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gamma-Aminobutyric Acid
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6-Cyano-7-nitroquinoxaline-2,3-dione
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Calcineurin
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Tacrolimus