Abstracts

Rationale. Atypical absence epilepsy in children is malignant and differs markedly from typical absence epilepsy in EEG findings, ictal behavior, and cognitive and behavioral outcome. We have developed an animal model of atypical absence epilepsy using a cholesterol synthesis inhibitor, AY 9944 (AY) which is administered during postnatal brain development in rats. GABABreceptor (GABABR)-mediated mechanisms may play a role in experimental typical absence epilepsy. Therefore we sought to test the hypothesis that GABABR also is involved in atypical absence epilepsy. Methods. Atypical absence epilepsy was induced in rats with a postnatal treatment regimen of AY. At P 55 GABABR gene expression was determined in the brains of AY-treated animals using in situ hypbridization. Also, we determined the EEG and behavioral effects of GABABR agonists in drug naive rats using depth electrodes and EEG video monitoring. Results. AY treatment resulted in permanent atypical absence epilepsy with slow spike-wave at 5 Hz. The onset and offset of ictal behavioral arrest was gradual and the animal could move during the seizure. There was a significant increase in GABABR1a and GABABR1b mRNA expression throughout the forebrain, but not in cerebellum in the rats with AY-induced atypical absence epilepsy. There was no change in R2 gene expression in the AY-treated animals. Administration of GABABR agonists resulted in acute atypical absence seizures which involved hippocampal as well as thalamocortical structures. Discussion. These data indicate that perturbed GABABR-mediated activity which involves the hippocampus, in addition to the thalamus and cortex, results in atypical absence epilepsy. In contrast, when altered GABABR function is restricted to thalamocortical circuitry typical absence epilepsy may result. Further, slow spike-waves were recorded from thalamocortical and hippocampal structures in both the AY model of atypical absence epilepsy and GABABR agonist-induced atypical absence seizures. The presence or absence of hippocampal involvement may define absence epilepsy as typical or atypical and the neurodevelopmental outcome as benign or malignant