Abstracts

The WAG/Rij rat is a valid genetic animal model of absence epilepsy. Spike-wave discharges (SWD) appear at age 3 months and increase during development until all rats show SWD in adulthood. Recently, it was found that WAG/Rij rats show an upregulation of sodium channels Nav1.1 and Nav1.6, and a downregulation of the hyperpolarization-activated cation channel HCN1, in the somatosensory cortex (SMS CTX) compared to non-epileptic control animals. Although these channel alterations could be directly involved in SWD generation, it is not clear whether they are the cause or effect of SWD., In a 1^st experiment, starting at P21, WAG/Rij and non-epileptic Wistar rats chronically received either ethosuximide (ETX) 300 mg/kg/d in drinking water or plain water. At 5 months of age the EEG was recorded and immunocytochemistry was performed for Nav1.1, Nav1.6 and HCN1 in SMS CTX. In a 2^nd experiment the above chronic ETX administration was repeated in another group of WAG/Rij rats, but this time ETX was discontinued at 5 months of age. EEG recordings were performed at 1, 14, 30 and 60 days after cessation of ETX, and compared to rats on continued ETX or normal drinking water., EEG recordings at 5 months of age confirmed the blockade of SWD with therapeutic ETX levels in both experiments. The immunocytochemistry showed that WAG/Rij rats that received ETX (n=12) had expression levels of Nav1.1, Nav1.6 and HCN1 in SMS CTX that were comparable to non-epileptic control animals (n=12), while untreated WAG/Rij rats (n=12) had an increase in Nav1.1, Nav1.6 and decrease in HCN1 expression. Furthermore, preliminary analysis of the 2^nd experiment shows that SWD are reduced even 60 days after cessation of ETX (n=15) when compared to untreated age matched controls (n=16). Interestingly, this seizure reduction is accompanied by the emergence of brief rhythmic discharges (resembling those normally seen in WAG/Rij rats during an early stage of SWD development around 3 months), that do not occur in animals in which ETX is continued (n=13)., Our data suggest that seizure activity is necessary for the abnormal expression of ion channels in WAG/Rij rats, and also that seizures may be necessary for the full expression of the epileptic phenotype. Thus, [apos]seizures beget seizures[apos] may apply even in genetic forms of epilepsy. These results hold the promising possibility that therapeutic interventions at an early stage may prevent seizure development in genetically susceptible individuals., (Supported by VA Medical and Rehabilitation Research Services, Paralyzed Veterans of America, and United Spinal Association (to S.G.W.); NIH NS 049307 and the Blattmachr Fund (to H.B.).)