Abstracts

Atypical absence seizures are an invariable component of Lennox Gastaut syndrome where they are associated with severe cognitive impairment (Farwell et al. Epilepsia 1985;26:395), but the relation of the seizures to the mental retardation is unknown. We have used an animal model of atypical absence seizures, the AY 9944 (AY) model to investigate this question. This model bears clinical and electrographic resemblance to the human condition (Cortez et al, Neurology 2001;56:341) including abnormal learning and memory. We have shown previously that while the seizures are blocked by anti-absence drugs such as ethosuximide, this drug does not reverse the learning deficits in this model (Chan et al. Pharmacol Biochem Behav 2004;190:328). The object of the following experiments was to test the hypothesis that a seizure-independent, gamma amino butyric acid (B) [GABA(B)] receptor-mediated mechanism underlies the learning impairment in the AY-model of atypical absence seizures. The AY model of atypical absence seizures was created as described (Cortez et al, 2001). Chronic epidural electrodes were surgically implanted after weaning for ECoG recording to quantify the total slow spike wave discharge (SSWD) duration. For behavioral learning and memory testing the spatial working and reference memory of AY-treated and control animals were evaluated in an eight-arm radial arm maze (RAM) (Chan et al. 2004). Long term potentiation (LTP) in hippocampal slice preparations from AY-treated animals and controls was done as described (Chan et al. 2004). A graduated series of doses of the GABA(B) receptor antagonist, 3-aminopropyl(diethoxymethyl)phosphinic acid [CGP 35348 (CGP)]) or 0.9% NaCl was administered to AY-treated animals prior to either RAM testing, ECoG recordings, or sacrifice for LTP recordings. High doses of CGP blocked SSWD and reversed the learning deficits in the AY-treated animals. Low doses of CGP failed to alter the SSWD duration in AY-treated animals; however, the dose of CGP that had no effect on AY-induced atypical absence seizures resulted in a significant improvement in the spatial memory task which recovered in the low dose CGP/AY group to the level of the non-epileptic control group. Similarly, the impaired LTP observed in the AY controls, also was restored to control baseline in the presence of low dose CGP in rats with AY-induced atypical absence seizures. The data suggest that the cognitive impairment in the AY model of atypical absence seizures is independent of the SSWD and raise the possibility that GABA(B) receptor antagonists (Froestl et al. Biochem Pharmacol 2004;68:1479) may have clinical utility in treatment of both atypical absence seizures (high dose) and deficits in cognition (low dose) in children with Lennox Gastaut syndrome. (Supported by Canadian Institutes of Health Research.)