Abstracts

Rationale: Acute and chronic seizures have been shown to be influenced by circadian rhythms in both human and animal models of epilepsy (Ferrillo et al, Clin Neurophysiol, 2000; Staba et al, J Neurosci, 2002; Asano et al, Clin Neurophysiol, 2007). Moreover, seizures themselves are known to perturb circadian rhythms in animal models (Stewart & Lueng, Epilepsy Behav., 2003), although it is unknown whether these changes are permanent and if treatment of the underlying epilepsy restores circadian function. We asked whether 1) chronically epileptic mice have impaired circadian function, 2) seizure activity is characterized by circadian rhythmicity and 3) treatment with the anticonvulsant ketogenic diet (KD) can reverse such perturbations. Methods: Chronically epileptic Kcna1-null mice were fed either a standard diet (SD) or ketogenic diet (KD) ad libitum for 4 wks beginning on postnatal day 18. Following parasagittal electrode- and subcutaneous wireless transmitter implantation and a 3-day recovery period, animals underwent continuous video-EEG (Stellate Systems, Quebec; Data Sciences Int’l, St. Paul, MN) and actigraphy (Mini Mitter Co., Bend, OR) monitoring for 3-5 consecutive days. All mice were housed in a quiet room with a 12h light/dark cycle. Results: Seizure activity in Kcna1-null mice peaked during subjective night at 08:18 ± 1.52 hr (N=9) and exhibited circadian periodicity with the fewest seizures occurring at 20:00 hr. We also observed significant disruption in the circadian rhythms of epileptic mice. Peak activity for wild type mice occurred at 21:27 ± 0.28 hr (ranging from 20:26 - 22:51 hr, N=9). In contrast to this 2.4 hr range, peak activity for chronically epileptic mice was more unpredictable, occurring during a 12.4 hr range (12:33 - 24:57 hr). Interestingly, these mice could be further divided into two populations. Peak activity was delayed to 23:25 ± 0.38 hr (p<0.005) in 6/9 epileptic mice, while in 3/9 mice activity was advanced, peaking at 16:00 ± 1.26 hr (p<0.005) when compared to wild-type mice. Treatment with the KD abolished seizure periodicity and restored circadian function; activity peaked at 22:44 ± 0.67 hr (p=0.07 when compared to wild-type mice) and the range narrowed to 4.6 hr (20:15 - 24:51 hr, N=7).