Chronic atypical absence
seizures are a component of the
Lennox-Gastaut syndrome, a disorder invariably associated with severe
cognitive impairment in children. However, the cause of this intellectual delay remains unclear. The
AY9944 model of chronic atypical absence
seizures in rats reliably reproduces the electrographic, behavioral, pharmacological and cognitive features of clinical atypical absence. Using this model, we tested the hypothesis that the
cognitive impairment associated with this disorder involves a
gamma-aminobutyric acid B (
GABA(B)) receptor-mediated mechanism. Therefore, we examined the effect of a specific, high affinity
GABA(B) receptor antagonist, CGP35348, on the atypical absence
seizures, the working memory deficits, and the altered long-term potentiation that we have observed in the
AY9944 model. CGP35348 blocked atypical absence
seizures, restored long-term potentiation to normal level, and reversed the cognitive deficit in the AY9944-treated animals. However, dose-response studies showed that lower doses of CGP35348 that failed to influence atypical
absence seizure activity, completely reversed the spatial working memory deficit. These data suggest that
GABA(B) receptor-mediated mechanisms are responsible for the
cognitive dysfunction in the
AY9944 model of chronic atypical absence
seizures and further, that their
cognitive impairment is independent of the seizure activity. The data raise the possibility that
GABA(B) receptor antagonists may have therapeutic potential for the treatment of
cognitive impairment in
epilepsy syndromes where atypical absence
seizures are a component.