Abstracts

Rationale: Early childhood is commonly when absence epilepsy presents. The brain may undergo changes during a developmental window that leads to the chronic epileptic state. Disruption of this pro-epileptic organization through intervention during this critical window may be possible, and could ultimately lead to prevention of epilepsy. Recent work in our laboratory demonstrated that early intervention with antiepileptic medication during development causes adult WAG/Rij rats, an established model of human absence epilepsy, to have reduced seizures off medication. C3H/HeJ mice display spontaneous spike-and-wave discharges (SWD), and are a model of human absence epilepsy, but have the advantage of an identified causative genetic defect. Methods: The effectiveness of chronic seizure suppression in C3H/HeJ mice was investigated using different antiepileptic drugs, including ethosuximide and sodium valproate and different routes of administration; via drinking water, via osmotic mini-pumps implanted subcutaneously, and intracerebroventricularly using brain infusion cannulas with osmotic pumps. The natural development of seizures in mice from five days after birth to adulthood was also investigated, as was the variability of seizure frequency with circadian rhythm, age, and gender. Results: Administration of ethosuximide via drinking water even at very high doses did not provide a significant reduction in seizure frequency. Seizures were reduced by subcutaneous administration of sodium valproate or ethosuximide at variable doses using mini-pumps, but this effect was not sustained. Administration of ethosuximide at variable doses via intracerebroventricular cannula with mini-pumps was successful in reducing the seizure frequency. Typical SWD begin between p15 and p20 in C3H/HeJ mice, without gender differences. A circadian pattern is observed with increased SWD in the dark phase similar to other rodent models. Conclusions: The C3H/HeJ model can be used to investigate the effects of chronic seizure suppression on anti-epileptogenesis. Sustained seizure suppression was not observed with oral and subcutaneous administration of medications, likely due to very rapid murine hepatic metabolism of drugs. Administration via intracerebroventricular cannula appears promising, and will provide a useful model for investigations of the genetic and molecular changes associated with epileptogenesis. Ultimately, this work, may lead to a cure for human absence epilepsy, and other more severe epilepsy disorders, by targeting the development of the disease rather than treating the symptoms. Acknowledgements: This work was supported by NIH R01 NS049307, P30 NS052519 (HB), the Howard Hughes Medical Institute Medial Fellows Program (DE), and by the Betsy and Jonathan Blattmachr family.