Abstracts

Rationale: : Cognitive impairment is increasingly becoming recognized as a significant co-morbidity in patients with epilepsy. This widespread problem is believed to be secondary to the etiology, severity of the disease state, and/or chronic anti-epileptic drug (AED) treatment. The underlying mechanisms leading to AED-induced cognitive dysfunction remain unclear. In contrast, there is emerging clinical data to suggest that the ketogenic diet (KD) may ameliorate memory dysfunction in epilepsy patients. In the present study, we assessed the effects of the KD vs. standard AEDs on seizure frequency and learning/memory function in a developmental animal model of epilepsy. Methods: Spontaneously epileptic Kcna1-null (KO) mice were generated using heterozygous breeding pairs. KD (Bio-serv F3666) and AEDs [carbamazepine (CBZ, 40mg/kg/day, mixed with methylcellulose [MC] as the vehicle), phenobarbital (PB, 30 mg/kg/day, mixed with saline)] were respectively administrated ad libitum and intraperitoneally for 2 weeks (all treatments began at postnatal day 21; KD n=6, SD n=5, CBZ n=4, MC n=4, PB n=4). Control groups of KO mice fed a standard diet (SD) were injected with either saline or methylcellulose alone. After 7-10 days of treatment, each animal underwent 72 hrs of continuous video-EEG monitoring. Long-term potentiation (LTP) was evoked in hippocampal slices acutely prepared from all treatment groups with either high frequency stimulation (HFS, 100 Hz, 1 sec) or theta-burst stimuli (TBS, consisting of 5 trains delivered at 0.2 Hz). Results: SD-fed KO mice exhibited a mean daily tonic-clonic seizure frequency of 5.5 0.8. No significant differences were found between KO/SD and KO/CBZ groups; in contrast, KO/KD and KO/PB groups exhibited significantly decreased seizure frequencies compared to both KO/SD and KO/CBZ cohorts (p<0.01). Intact hippocampal CA1 LTP responses were seen in wild-type (WT) mice fed a SD, in contrast to KO/SD animals where intrinsic impairment of LTP was observed. Interestingly, neither PB nor CBZ restored the intrinsically impaired LTP responses in KO mice. In contrast, KO/KD animals showed a prominent reversal of LTP dysfunction. Methylcellulose had no effect on LTP, but CBZ alone worsened LTP maintenance in WT mice. Remarkably, the synaptic protective effects of the KD were still observed after cessation of KD treatment.