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.
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Authors | Russell M Sanchez, Weimin Dai, Rachel E Levada, Jocelyn J Lippman, Frances E Jensen |
Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience
(J Neurosci)
Vol. 25
Issue 13
Pg. 3442-51
(Mar 30 2005)
ISSN: 1529-2401 [Electronic] United States |
PMID | 15800199
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Excitatory Amino Acid Antagonists
- Receptors, AMPA
- Receptors, GABA-A
- gamma-Aminobutyric Acid
- 6-Cyano-7-nitroquinoxaline-2,3-dione
- Calcineurin
- Tacrolimus
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Topics |
- 6-Cyano-7-nitroquinoxaline-2,3-dione
(pharmacology)
- Animals
- Animals, Newborn
- Blotting, Western
(methods)
- Calcineurin
(physiology)
- Dose-Response Relationship, Radiation
- Electric Stimulation
(methods)
- Excitatory Amino Acid Antagonists
(pharmacology)
- Excitatory Postsynaptic Potentials
(drug effects, physiology, radiation effects)
- Gene Expression Regulation, Developmental
(drug effects, physiology)
- Hippocampus
(growth & development, pathology, physiopathology)
- Hypoxia
(complications)
- Immunoprecipitation
(methods)
- In Vitro Techniques
- Neural Inhibition
(drug effects, physiology, radiation effects)
- Patch-Clamp Techniques
(methods)
- Rats
- Receptors, AMPA
(physiology)
- Receptors, GABA-A
(metabolism)
- Seizures
(etiology, metabolism, physiopathology)
- Synapses
(metabolism)
- Synaptic Transmission
(physiology)
- Tacrolimus
(pharmacology)
- Time Factors
- gamma-Aminobutyric Acid
(metabolism)
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