The substantia nigra pars reticulata, the area with the highest expression of ATP-sensitive potassium channels in the brain, plays a pivotal role in suppressing the propagation of generalized seizures by its silence. Mice lacking the Kir6.2 subunit of the channels were extremely susceptible to generalized seizures after brief hypoxia. The nigral neuron activity, which is among highest in the brain, was rapidly inactivated during hypoxia by the opening of the post-synaptic ATP-sensitive potassium channels in normal mice, while the neuron activity was enhanced in the mutant mice. During seizure, the cerebral metabolic rate of oxygen increases more than under any other circumstance, leading ultimately to irreversible cell damage. Thus, rapid minimization of energy consumption during metabolic stresses such as hypoxia may be effective protection from the seizure-induced lethal effects. The ATP-sensitive potassium channels in the reticulata neurons may be involved in the protection mechanism against energy-consuming generalized seizure by earlier response to hypoxia than those in other, less active neuron types.