Abstracts

Rationale: We have previously shown an activity-dependent decrease in Kv4.2 channels in brain from epileptic rats, which was associated with an increase in neuronal excitability. Kv4.2 channels contribute to the regulation of the myocyte action potential in rodents. Retrospective studies have demonstrated increased heart rate in epileptic humans that experienced sudden unexpected death in epilepsy. We propose that there are changes in heart rate in epileptic rodents and associated activity-dependent remodeling of myocardial Kv4.2 channels. Furthermore, we propose that deficiency of Kv4.2 channels is a risk factor for sudden death in rodents.Methods: Western blotting with K+ channel antibodies was performed on myocardial membranes prepared from epileptic and sham rats. Video-EEG and EKG recordings were performed. Convulsant stimulation was performed in Kv4.2 knockout, forebrain selective Kv4.2 dominant negative and wildtype mice. The time to onset of seizures, status epilepticus and survival was assessed in all groups.Results: Myocardial Kv4.2 levels were decreased in epileptic compared to sham animals (p<0.05). Kv4.3 was also significantly decreased (p<0.05), while Kv1.5 and Kv4.1 levels were not significantly altered. The mean resting heart rate was significantly higher in epileptic compared to sham animals (p<0.05). Both Kv4.2 knockout and forebrain selective Kv4.2 dominant negative mice had decreased latencies to first seizure and status epilepticus compared to wildtype mice (p<0.05). Interestingly, we also observed that 100% of Kv4.2 knockout mice died following convulsant-induced status epilepticus, while the forebrain selective Kv4.2 dominant negative transgenic and wildtype mice survived status epilepticus.Conclusions: Our findings suggest that there is activity-dependent remodeling of Kv4 channels in hippocampus and myocardium in a rodent epilepsy model. Furthermore, our studies reveal that Kv4.2 knockout is associated with a lower seizure threshold and increased risk for sudden death with convulsant stimulation, while mice expressing a the forebrain selective dominant-negative Kv4.2 construct did not exhibit sudden death despite a lower seizure threshold compared to wildtype mice. These findings support the possibility that ion channel remodeling occurs in epilepsy and may be a risk factor contributing to sudden death in epilepsy.