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The Journal of Neuroscience, November 1, 1999, 19(21):9412-9425
Unilateral GluR2(B) Hippocampal Knockdown: A Novel Partial Seizure Model in the Developing Rat
Linda K. Friedman1, 2 and Alexei R. Koudinov3 1 Department of Neuroscience, Seton Hall University, South Orange, New Jersey 07079, Department of Neuroscience, New Jersey Neuroscience Institute, Edison, New Jersey, 2 Albert Einstein College of Medicine, Bronx, New York, and 3 Department of Neurobiology, Weizmann Institute, Rehovot, Israel
Kainic acid (KA) induces status epilepticus in both adult and young rats but with different consequences on pathology and gene expression. In adults, GluR2(B) AMPA subunit expression is markedly reduced in CA3 neurons before neurodegeneration. In pups, the GluR2(B) subunit is sustained, possibly contributing to neuronal survival. Mechanisms underlying the reduced vulnerability of developing neurons to seizures was investigated by examining the effects of unilateral microinfusions of GluR2(B) antisense oligodeoxynucleotides (AS-ODNs) into the hippocampus of young rats in the presence or absence of a subconvulsive dose of KA. GluR2(B) AS-ODN infusions resulted in spontaneous seizure-like behavior, high stimulus intensity population spikes in the absence of long-term potentiation, and neurodegeneration of CA3 neurons lateral to the infusion site. Electroencephalography revealed paroxysmal activity and high-frequency high-amplitude discharges associated with vigorous and continuous scratching, wild running, or bilateral jerking movements. Pups lacking phenotypic behavior exhibited high-rhythmic oscillations and status epilepticus by the dose of KA used. Radiolabeled AS-ODNs accumulated throughout the ipsilateral dorsal hippocampus. GluR2(B) but not GluR1(A) receptor protein was markedly reduced after GluR2(B) knockdown. In contrast, GluR1(A) knockdown reduced GluR1(A) but not GluR2(B) protein without change in behavior or morphology. Therefore, unilateral downregulation of hippocampal GluR2(B) but not GluR1(A) protein reduces the seizure threshold and survival of CA3 neurons in the immature hippocampus, possibly providing a novel partial seizure model in the developing rat.
Key words: epilepsy; development; GluR2(B); knockdown; hippocampus; neurodegeneration
Copyright © 1999 Society for Neuroscience 0270-6474/99/19219412-14$05.00/0
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