Knockout of sodium pump α3 subunit gene (Atp1a3-/-) results in perinatal seizure and defective respiratory rhythm generation.

ATP1A3 encodes a neuron-specific human α3 subunit isoform of the sodium pump that plays an important role in neuronal excitability. Point and deletion mutations in ATP1A3 have been recognized in diverse neurological disorders. Three ATP1A3 disorders, alternating hemiplegia of childhood (AHC); apnea; and severe infantile epileptic encephalopathy often appear shortly after birth. To gain insight into the pathophysiology of these disorders and to understand the functional roles of the sodium pump α3 subunit in the brain in vivo during this period of development, we examined the phenotype of Atp1a3 knockout homozygous mouse fetuses (Atp1a3-/-). We focused on fetuses just before birth because at birth, about half of them showed severe seizure, and none could continue effective breathing and died soon after birth, without any gross anatomical anomalies. We examined c-Fos expression in the brains of Atp1a3-/- and found a significantly increased number of c-Fos-expressing cells in various regions of the brains, with unique distribution in the cerebellum, when compared with wild-type littermates (Atp1a3+/+). We also measured contents of monoamine neurotransmitters in the brains and found higher contents, especially of dopamine and noradrenaline, in the brains of Atp1a3-/- compared with those of Atp1a3+/+. In addition, we found various abnormal respiratory rhythms produced in the brainstem of Atp1a3-/-. These results suggest that Atp1a3 plays a critical role in neural function during development and at birth.