Abstracts

Early in development the brain shows greater plasticity and increased seizure susceptibility. Many of the neurotransmitter systems are more heavily weighted toward excitability. The mechanisms that are in place to dampen excitability early in life are not well characterized. Many of the K+ channels known to regulate excitability in the mature brain are minimally expressed early in development. The studies presented here evaluate the pattern of Kv4.2 expression in developing rodent hippocampus and evaluate the role of Kv4.2 channels in the regulation of seizure susceptibility during development. Kv4.2 channels contribute to the transient, A-type K+ current which dampens the back-propagating action potential in hippocampal pyramidal dendrites and thus are considered critical regulators of post-synaptic excitability. The role of Kv4.2 channels in regulating excitability in immature brain has not been examined., In the studies presented here we characterized Kv4.2 subunit protein expression levels in hippocampus at postnatal day (PD) 5, 10, 15, 25, and 90. In addition, we examined whether mice deficient in Kv4.2 channels early in development were more susceptible to kainate-induced seizures and status epilepticus than wildtype animals. For these studies, we administered kainate (5 mg/kg IP) to PD 10 wildtype (WT) and Kv4.2 KO mice. Seizure activity was assessed behaviorally (Racine Scale). Following the development of SE the animals were given pentobarbital (5 mg/kg SC) and allowed to survive. On PD 30 we implanted electrodes in the hippocampus and cortex of KO and WT mice and recorded video-EEG to determine whether the animals developed spontaneous seizures following kainate-induced SE., Kv4.2 channel expression was seen early during postnatal development (by PD 5) in hippocampus. At all of the developmental time points assessed, there was no significant difference in hippocampal Kv4.2 protein levels when compared to adult (PD 90) levels of Kv4.2. On PD10, KO mice had a statistically significant earlier onset to first behavioral seizure (p[lt]0.01) and an earlier onset to behavioral status epilepticus (p[lt]0.05) compared to WT. Pilot video-EEG studies revealed that KO and WT mice do not develop spontaneously recurring seizure activity. One important long-term consequence of early-life seizures is behavioral deficits. Thus, investigations are currently underway to evaluate whether there are differences in the behavioral deficits following early-life seizures in the KO compared to WT mice., In summary, our findings suggest that in hippocampus Kv4.2 channels are expressed early during development and thus likely play an important role in the regulation of excitability in this region of the developing brain. Furthermore, our studies using Kv4.2 KO mice suggest that Kv4.2 channels play a role in the regulation of seizure susceptibility in the immature brain., (Supported by NINDS/NIH, Society for Neuroscience, Partnership for Pediatric Epilepsy Research.)