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The Journal of Neuroscience, August 6, 2008, 28(32):7979-7990; doi:10.1523/JNEUROSCI.1734-08.2008

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Development/Plasticity/Repair
Early Alterations of AMPA Receptors Mediate Synaptic Potentiation Induced by Neonatal Seizures

Sanjay N. Rakhade,^1,2 * Chengwen Zhou,^1,2 * Paven K. Aujla,¹ Rachel Fishman,¹ Nikolaus J. Sucher,^1,2 and Frances E. Jensen^1,2,3

¹Department of Neurology, Division of Neuroscience, Children's Hospital, Boston, Massachusetts 02115, and ²Department of Neurology and ³Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Frances E. Jensen, 300 Longwood Avenue, Enders 348, Children's Hospital and Harvard Medical School, Boston, MA 02115. Email: Frances.Jensen{at}childrens.harvard.edu

The highest incidence of seizures during lifetime is found in the neonatal period and neonatal seizures lead to a propensity for epilepsy and long-term cognitive deficits. Here, we identify potential mechanisms that elucidate a critical role for AMPA receptors (AMPARs) in epileptogenesis during this critical period in the developing brain. In a rodent model of neonatal seizures, we have shown previously that administration of antagonists of the AMPARs during the 48 h after seizures prevents long-term increases in seizure susceptibility and seizure-induced neuronal injury. Hypoxia-induced seizures in postnatal day 10 rats induce rapid and reversible alterations in AMPAR signaling resembling changes implicated previously in models of synaptic potentiation in vitro. Hippocampal slices removed after hypoxic seizures exhibited potentiation of AMPAR-mediated synaptic currents, including an increase in the amplitude and frequency of spontaneous and miniature EPSCs as well as increased synaptic potency. This increased excitability was temporally associated with a rapid increase in phosphorylation at GluR1 S845/S831 and GluR2 S880 sites and increased activity of the protein kinases CaMKII (calcium/calmodulin-dependent protein kinase II), PKA, and PKC, which mediate the phosphorylation of these AMPAR subunits. Postseizure administration of AMPAR antagonists NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline), topiramate, or GYKI-53773 [(1)-1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine] attenuated the AMPAR potentiation, phosphorylation, and kinase activation and prevented the concurrent increase in in vivo seizure susceptibility. Thus, the potentiation of AMPAR-containing synapses is a reversible, early step in epileptogenesis that offers a novel therapeutic target in the highly seizure-prone developing brain.

Key words: AMPA receptor; epilepsy; intracellular signaling; neonatal; postsynaptic; synaptic plasticity

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Received April 21, 2008; revised June 25, 2008; accepted June 26, 2008.

Correspondence should be addressed to Dr. Frances E. Jensen, 300 Longwood Avenue, Enders 348, Children's Hospital and Harvard Medical School, Boston, MA 02115. Email: Frances.Jensen{at}childrens.harvard.edu

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