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The Journal of Neuroscience, March 30, 2005, 25(13):3442-3451; doi:10.1523/JNEUROSCI.0204-05.2005

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Development/Plasticity/Repair
AMPA/Kainate Receptor-Mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain

Russell M. Sanchez,^1 * Weimin Dai,^2 * Rachel E. Levada,² Jocelyn J. Lippman,² and Frances E. Jensen^2,3

¹Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, Texas 78229-3900, ²Department of Neurology, Children's Hospital and Harvard Medical School, and ³Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115

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_AR)-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_AR inhibition were attenuated by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] or Joro spider toxin. GABA_AR 2/3 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.

Key words: glutamate receptors; GABA_A receptors; calcium; epilepsy; hypoxia; FK-506

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Received Dec 29, 2003; revised February 16, 2005; accepted February 17, 2005.

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