Abstracts

Rationale: The oldest known treatment option for the control of seizures is the use of fasting or starvation. Under normal conditions, the brain’s primary source of energy is almost exclusively glucose but during periods of starvation the brain can utilize ketones that are produced in the liver by the oxidation of fatty acids. In the early 1920s Russell Wilder demonstrated that the anticonvulsant effects of starvation could be obtained by maintaining a diet of high fat and low protein/carbohydrate intake which is now commonly referred to as the ketogenic diet. The ketogenic diet has been an effective antiepileptic treatment dating back to the mid-1920s. While a number of hypotheses have been advanced, the exact cellular mechanism that underlies the antiepileptic action of the ketogenic diet remains unclear. At the same time, evidence has been accumulating that ketones can directly enhance voltage-gated potassium currents gated by potassium channel complexes that contain Kvβ2 auxiliary sub-units which themselves possess an aldo-keto reductase enzymatic core domain. Therefore, we advance the novel hypothesis that ketones generated under ketogenic conditions directly interact with Kvβ auxiliary sub-units to increase voltage-gated potassium currents which in turn reduces neuronal excitability.Methods: At 8 weeks of age, wild-type (WT) and Kvβ2-/- mice were separated into two groups, one of which was fed standard chow, and the other which was fed a ketogenic diet in which 85% of the daily caloric intake was derived from fat. Each group was left on its respective diet for a total of 6 weeks before experiments were started. Ex vivo hippocampal slices were prepared from WT and Kvβ2-/- animals on both normal chow and the ketogenic diet. In vitro extracellular field potential recordings were made in normal artificial cerebrospinal fluid aCSF at ~32 degree. Epileptiform bursts were induced by removing Mg2+ and increasing K+ concentrations in the aCSF. The latency to the first burst as well as burst frequency and inter-burst interval were measured for at least one hour after perfusion with the modified aCSF.Results: Ictal events were observed in 100% of the slices prepared from WT mice that were maintained on the normal diet. Similarly, 100% of the slices prepared from Kvβ2-/- mice exhibited ictal events. However the latency to the first event was significantly shorter in the Kvβ2-/- mice. Only 50% of slices prepared from WT mice that were treated with the ketogenic diet exhibited repeated ictal activity. Conversely, 78% of Kvβ2-/- slices exhibited ictal bursting behavior.Conclusions: These results suggest that similar to its effect in vivo, the ketogenic diet reduces seizure-like activity in ex vivo slices. Furthermore, deletion of the Kvβ2 auxiliary sub-unit appears to diminish the beneficial effects of the ketogenic diet. Taken collectively, these results suggest that the Kvβ2 auxiliary sub-unit may be a physiological target of the ketogenic diet and acts to modulate neuronal excitability.