Abstracts

Kv4.2 subunits are thought to compose hippocampal A-type dendritic K⁺ currents, which regulate excitability through dampening back-propagating action potentials in dendrites. In several models of limbic epilepsy, Kv4.2 channel protein is downregulated. In order to investigate whether a decrease in Kv4.2 channels contributes to altered seizure threshold, we studied seizure susceptibility of Kv4.2 null mutants. Kainate (20 or 40mg/kg IP) or vehicle was administered to Kv4.2 null and wildtype (WT) mice. Seizure activity was assessed and scored according to the Racine Scale by monitoring visually for behavioral seizures. An additional group of mutant and wildtype mice were monitored with video EEG after administration of kainate (40mg/kg IP) or vehicle. Following the development of status epilepticus animals were treated with pentobarbital (15mg/kg) and allowed to survive. Video EEG monitoring was obtained at various time points following kainate administration to assess for the development of spontaneous seizures and spike activity. Kainate 20mg/kg induced behavioral seizures (Class 3 seizures [ndash] forelimb clonus), but not behavioral status epilepticus (recurrent Class 5 seizures [ndash] rearing and falling) in the Kv4.2 null and WT mice. The latency to onset of the first Class 3 seizures was significantly decreased (p[lt]0.05) and the frequency of Class 3 seizures was significantly increased (p[lt]0.05) in the Kv4.2 null compared to WT mice. The response to kainate 40mg/kg was also tested and revealed a similar increase in the frequency of Class 3 seizures in the Kv4.2 null compared to WT mice (p[lt]0.05), but animals in both groups had behavioral seizures consistent with status epilepticus. In a third group of animals with cortical and hippocampal EEG electrodes implanted, we assessed the response to kainate 40mg/kg or vehicle using video EEG monitoring. Kv4.2 null mice developed prolonged electrographic status epilepticus, requiring pentobarbital treatment. In contrast, the WT mice had a shorter period of status epilepticus, which was self-limited and did not require anticonvulsants. EEG monitoring up to two weeks following kainate administration revealed the presence of occasional electrographic seizures and frequent interictal spikes in the Kv4.2 null compared to no seizures and rare spikes in the WT mice. Monitoring with video EEG at longer time points following kainate is planned. Our results demonstrate that there is increased seizure susceptibility in the Kv4.2 null compared to WT mice. These observations support the idea that the decrease in Kv4.2 channels observed in chronically epileptic animals may contribute to hyperexcitability and potentially seizure activity. (Supported by NINDS/NIH, Epilepsy Foundation, and Child Neurology Foundation.)