Adenosine triphosphate (ATP)–sensitive potassium (K_ATP) channels are activated by various metabolic stresses, including hypoxia. The substantia nigra pars reticulata (SNr), the area with the highest expression of K_ATPchannels in the brain, plays a pivotal role in the control of seizures. Mutant mice lacking the Kir6.2 subunit of K_ATP channels [knockout (KO) mice] were susceptible to generalized seizures after brief hypoxia. In normal mice, SNr neuron activity was inactivated during hypoxia by the opening of the postsynaptic K_ATPchannels, whereas in KO mice, the activity of these neurons was enhanced. K_ATP channels exert a depressant effect on SNr neuronal activity during hypoxia and may be involved in the nigral protection mechanism against generalized seizures.