Abstracts

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a seizure disorder associated with specific point mutations in the [alpha]4 and [beta]2 subunits of the neuronal nicotinic acetylcholine receptors (nAChRs). Attempts to examine the effects of these mutations on the functioning of nAChRs in heterologous systems have provided conflicting results, suggesting that proper analysis of the effects of these mutations on network excitability requires an adequate in vivo model. To fully examine possible mechanisms underlying ADNFLE, we characterized the electrographic phenotype in two ADNFLE mouse models ([alpha]4S252F and [alpha]4+L264)., We implanted adult male WT and ADNFLE mutant mice with chronic EEG recording electrodes overlying the frontal lobes. Electroencephalogram (EEG) recordings were collected every day for 4-8 hours. Electrographic seizure events were defined as changes in the amplitude and frequency of the EEG signal. Seizure susceptibility was measured as cumulative time seizing expressed as a fraction (%) of the total recording time, and the average duration of individual electrographic events. To determine the contribution of GABAergic inhibition in driving network excitability, low dose picrotoxin (0.1mg/kg) was administered i.p. in sterile injection saline., ADNFLE mutant mice exhibit abnormal cortical EEG characterized by persistent delta and theta activity. In addition, both the [alpha]4S252F and [alpha]4+L264 ADNFLE mutant mice exhibit spontaneous seizures (21.5 +/- 12.0 and 8.4 +/- 3.5 % time seizing, respectively). Administration of the GABAA receptor antagonist picrotoxin at a dose (0.1mg/kg) with no discernible effects on WT mice, in the ADNFLE mutants significantly decreased the power of the abnormal baseline EEG activity and abolished seizure activity., This is the first mouse model of ADNFLE which exhibits spontaneous seizure events. Our results are consistent with the idea that GABAergic synchrony drives both the increased delta and theta basal EEG activity and seizure generation in ADNFLE mutants. Thus, a new and counterintuitive therapeutic approach in ADNFLE may the administration of low level GABAergic antagonists to prevent synchrony and seizures in ADNFLE patients., (Supported by NIH Grants NS30549, NS02808, and the Coelho Endowment to I.M. J.M was also supported by a postdoctoral fellowship from the Epilepsy Foundation of America (EPILEPSY 05030663).)