Document Detail

AMPA/kainate receptor-mediated downregulation of GABAergic synaptic transmission by calcineurin after seizures in the developing rat brain.
MedLine Citation:
PMID:  15800199     Owner:  NLM     Status:  MEDLINE    
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.
Russell M Sanchez; Weimin Dai; Rachel E Levada; Jocelyn J Lippman; Frances E Jensen
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  25     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-03-31     Completed Date:  2006-03-23     Revised Date:  2010-06-10    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3442-51     Citation Subset:  IM    
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
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MeSH Terms
6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
Animals, Newborn
Anoxia / complications
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
Immunoprecipitation / methods
Neural Inhibition / drug effects,  physiology,  radiation effects
Patch-Clamp Techniques / methods
Receptors, AMPA / physiology*
Receptors, GABA-A / metabolism
Seizures / etiology,  metabolism,  physiopathology
Synapses / metabolism*
Synaptic Transmission / physiology*
Tacrolimus / pharmacology
Time Factors
gamma-Aminobutyric Acid / metabolism*
Grant Support
Reg. No./Substance:
0/Excitatory Amino Acid Antagonists; 0/Receptors, AMPA; 0/Receptors, GABA-A; 109581-93-3/Tacrolimus; 115066-14-3/6-Cyano-7-nitroquinoxaline-2,3-dione; 56-12-2/gamma-Aminobutyric Acid; EC
Comment In:
Epilepsy Curr. 2005 Nov-Dec;5(6):234-5   [PMID:  16372059 ]

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