The Natural History and Treatment of Epilepsy in a Murine Model of Tuberous Sclerosis

Summary: Purpose: Patients with tuberous sclerosis complex (TSC) often have severe epilepsy that is intractable to available therapies. The development of novel treatments for epilepsy in TSC would benefit greatly from a suitable animal model, but most animal models of TSC to date have few reported neurological abnormalities, such as epilepsy. We previously described a novel model of TSC, due to conditional inactivation of the Tsc1 gene in glia (Tsc1GFAPCKO mice), in which mice develop epilepsy and premature death. Here, we characterize the natural history of the epilepsy in Tsc1GFAPCKO mice in more detail and report acute effects of treatment with standard antiepileptic drugs on seizures in these mice. Methods: Video-EEG recordings were obtained from Tsc1GFAPCKO mice on a weekly basis, starting at 4 weeks of age until death, to monitor progression of interictal EEG abnormalities and seizures. In separate experiments, Tsc1GFAPCKO mice were monitored for interictal EEG abnormalities and seizures before and during treatment with phenobarbital, phenytoin, or saline. Results: Tsc1GFAPCKO mice developed seizures around 4–6 weeks of age and subsequently had progressive worsening of the interictal EEG background and seizure frequency over a month, culminating in death. Treatment with phenobarbital or phenytoin caused a reduction in seizure frequency, but did not improve EEG background or prevent death. Conclusions: Tsc1GFAPCKO mice develop progressive epilepsy. Acute treatment with standard antiepileptic drugs suppresses seizures in these mice, but does not affect long-term prognosis. Tsc1GFAPCKO mice represent a good model to test other drugs that may have true antiepileptogenic actions in TSC.