Abstracts

Kainate receptors have been implicated in the pathogenesis of epilepsy and contribute to seizures in hippocampal area CA3. The epileptogenic effect of these receptors may result from their ability to both reduce GABAergic inhibition and directly excite principal cells. Kainate receptors are comprised of a family of subunits, including GluR5-7 and KA1 and KA2, the combination of which determines the pharmacological and physiological properties of the receptor. The KA1 and KA2 subunits do not form functional channels by themselves but modify the properties of the channel-forming subunits. Recent work has indicated that kainate receptors containing KA subunits serve distinct functional roles in hippocampal circuits. Furthermore, these subunits confer upon kainate receptors a greatly heightened sensitivity to inhibition by zinc. Changes in the expression of kainate receptor subunits following pilocarpine-induced status epilepticus may contribute to the development of epilepsy. Microdissected tissue from the principal cell layers of the dentate gyrus, area CA3 and area CA1 was obtained from young adult rats 3 days after pilocarpine-induced status epilepticus or sham treatment. Real time RT-PCR using selective primers was used to quantify the level of mRNA for each kainate receptor subunit in the different hippocampal subregions. The RNA level of each kainate receptor subunit was normalized relative to that of neuron specific enolase. The normalized mRNA levels in pilocarpine treated rats were then expressed relative to that in sham treated animals. Field potential recordings from area CA3 of pilocarpine and sham treated rats were then used to determine whether changes in RNA levels of the kainate receptor subunits altered the function of synaptic kainate receptors. CA3 responses were evoked by mossy fiber stimulation. KA1 mRNA expression increased by 17 and 3 fold in the dentate and area CA3 respectively, following pilocarpine-induced status epilepticus. In contrast, KA2 mRNA levels in the dentate and CA3 decreased, being only 0.4 and 0.8 fold, respectively of control levels following pilocarpine treatment. KA2 mRNA levels in CA1 remained unchanged. GluR6 mRNA level in area CA3 doubled following pilocarpine treatment. In field potential recordings from hippocampal slices of pilocarpine-treated rats, the zinc sensitivity of the synaptic kainate response in CA3 was markedly reduced, as expected if the KA2 subunit confers high zinc sensitivity upon these receptors. These findings indicate dynamic changes in kainate receptor subunit expression during the period of epileptogenesis and suggest that decreases in the expression of the KA2 subunit might contribute to the seizure-induced loss of zinc sensitivity of kainate receptors in the mossy fiber pathway. Loss of this zinc-mediated inhibitory control following pilocarpine treatment could enhance excitability of neurons in area CA3. (Supported by NINDS (DM, RD) and NARSAD (DM).)