Possibly the most effective treatment for epilepsy is not a drug, but a dietary therapy - the ketogenic diet. Though this high fat/low carbohydrate and protein regimen is remarkably effective at reducing and even eliminating seizures, its exact mechanism remains unknown. One possibility that is currently being explored in Gary Yellen's lab is that the diet works via an effect of circulating ketone bodies on neuronal excitability. The specific hypothesis being explored in the Yellen lab is that a reduction in glycolytic ATP caused by the ketone bodies is acutely sensed by the ATP-inhibited potassium channel (KATP channel). Preliminary results show that when acute brain slices are exposed to the increase in ketone bodies seen during the ketogenic diet, there is a depression in spontaneous neuronal electrical activity, an effect that is abolished in the presence of KATP-specific blockers. This study will further test this hypothesis; first by recording from single isolated neurons while changing their metabolic state with ketone bodies, then by using an innovative optical technique, targeted luciferases, to investigate possible fluctuations in sub-cellular Iocalizations of ATP.
| Berg, Jim; Hung, Yin Pun; Yellen, Gary (2009) A genetically encoded fluorescent reporter of ATP:ADP ratio. Nat Methods 6:161-6 |
