Dysregulation of Sodium Channels in a Rat Model of Absence Epilepsy

Absence epilepsy is a generalized form of epilepsy where spike-wave discharges (SWDs) involve both hemispheres of the brain and thereby alter consciousness. Recent evidence by Meeren et al (2002) in the WAG/Rij rat model of absence epilepsy points to a cortical focus of SWDs before rapid generalization of the SWDs. This focus belongs in the peri-oral area of the somatosensory cortex, and it was found to consistently lead SWDs in other cortical and subcortical areas. With this recent finding, it seems plausible that a defect lies in this focal region of the cortex, leading to SWD in the WAG/Rij model. It is likely that an alteration of one or more ion channels leads to seizure generation in this rat model, as ion channels are what produce the hyperexcitability of seizures. In this study, our laboratory performed three consecutive days of scalp EEG recordings on WAG/Rij animals at different ages and compared this to control rat EEGs. As has been found before, we saw an increase in time spent in SWDs as the WAG/Rij animals aged. After completing EEG recordings, the animals were sacrificed and quantitative PCR and immunocytochemistry was performed on six regions of the cortex. In comparison to control animals, WAG/Rij rats had an increase in sodium channel subunits Nav1.1 and Nav1.6 in the region corresponding to the seizure focus identified by Meeren et al. In addition, as WAG/Rij rats aged, the amount of Nav1.1 and Nav1.6 also steadily increased in the peri-oral region of the somatosensory cortex. These findings suggest that specific sodium channelopathies may initiate SWD generation in this rodent model. The results of our study have many implications. Perhaps many, if not all, forms of human absence epilepsy are rooted in ion channelopathies which could be limited to specific regions of the brain. If this is so, and if the specific channelopathies are identified, it is also possible that very targeted therapies could be devised – either medically or surgically – to treat both “benign” and refractory absence epilepsies. Future studies are needed to determine whether the sodium channel dysregulation found in this rodent model is the cause or effect of SWDs and whether other channelopathies or dysregulation of channels exists. Our lab is currently looking at what effects ethosuximide, an anti-absence drug, has on sodium channel composition in the cortex of the WAG/Rij rat.