The sodium pump is the enzyme responsible for the maintenance of Na⁺ and K⁺ gradients across the cell membrane. Four isoforms of the catalyticα subunit have been identified, but their individual roles remain essentially unknown. To investigate the necessary functions of the α2 subunit in vivo, we generated and analyzed mice defective in the α2 subunit gene. Mice homozygous for the α2 mutation died just after birth and displayed selective neuronal apoptosis in the amygdala and piriform cortex. In these regions, high expression of c-Fos before apoptosis indicated neural hyperactivity, and re-uptake of glutamic acid and GABA into P₂ fraction containing crude synaptosome was impaired. These results indicate that the α2 subunit plays a critical role regulating neural activity in the developing amygdala and piriform cortex. Further supporting a role of theα2 subunit in the function of the amygdala, heterozygous adult mice showed augmented fear/anxiety behaviors and enhanced neuronal activity in the amygdala and piriform cortex after conditioned fear stimuli.