Metabolic Seizure Resistance via BAD and KATP Channels

Ketogenic diets are a very effective treatment for epilepsy. On a ketogenic diet, ketone bodies provide an alternative brain fuel, replacing much of the glucose ordinarily used by the brain. This change in fuel utilization may alter neuronal excitability and help produce the anticonvulsant effect of the diet. Brain fuel utilization can also be modified by a nondietary approach: genetic alteration of the protein BAD, which has known roles in regulating both apoptosis and glucose metabolism. When the metabolic function of BAD is genetically altered in mice, it produces reduced glucose metabolism and increased ketone body metabolism in neurons and astrocytes. This effect is related to regulation of BAD by phosphorylation and is independent of its apoptotic function. Mice with BAD modifications that produce a decrease in glucose metabolism exhibit strong resistance to behavioral and electrographic seizures in vivo. At the cellular level, BAD alteration leads to decreased seizurelike activity in the entorhinal cortex and hippocampus, two brain areas critical for seizure generation and propagation. BAD’s seizure protective effect is lost upon selective deletion of ATP-sensitive potassium (KATP) channels in the dentate gyrus, suggesting that KATP channels in this brain region may mediate BAD’s anticonvulsant effect.