How acute changes in the activity of neuronal mitochondrial affect learning and memory is unclear. By precluding mitochondrial localization of cannabinoid receptor 1 (CB1) in the mouse hippocampus, the authors prevented CB1-agonist-induced inhibition of excitatory transmission in hippocampal slices and of the poor performance of animals in the novel-object recognition test. Moreover, activation of mitochondrial CB1 decreased neuronal mitochondrial respiration. Together, these data show that acute alterations in mitochondrial activity can regulate memory formation.