UNILATERAL GLUR2 HIPPOCAMPAL KNOCKDOWN: A NOVEL PARTIAL SEIZURE MODEL IN THE DEVELOPING RAT

L.K. Friedman¹ and A.R. Koudinov²

1. Departments of Neuroscience, Seton Hall University, S Orange, NJ and NJ Neuroscience Institute Edison, NJ, Seton Hall University 400 S Orange Avenue S Orange, NJ. 07079

2. Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel

Kainic acid (KA) induces status epilepticus in adult and young rats but with different consequences on pathology and gene expression. In adults, GluR2 AMPA subunit expression is markedly reduced in CA3 neurons prior to neurodegeneration. In pups, the GluR2 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 AS-ODN infusions resulted in spontaneous seizure-like behavior, high stimulus intensity population spikes in the absence of long term potentiation (LTP), and neurodegeneration of CA3 neurons lateral to the infusion site. Electroencephalography (EEG) revealed high-rhythmical 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.  Therefore transient increases in the hippocampal GluR1(A):GluR2(B) protein ratio unilaterally reduce the seizure threshold and survival of CA3 neurons in the immature hippocampus, possibly providing a novel partial seizure model in the developing rat.

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