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Deficiency in Na,K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice.

Several disorders have been associated with mutations in Na,K-ATPase alpha isoforms (rapid-onset dystonia parkinsonism, familial hemiplegic migraine type-2), as well as reduction in Na,K-ATPase content (depression and Alzheimer's disease), thereby raising the issue of whether haploinsufficiency or altered enzymatic function contribute to disease etiology. Three isoforms are expressed in the brain: the alpha1 isoform is found in many cell types, the alpha2 isoform is predominantly expressed in astrocytes, and the alpha3 isoform is exclusively expressed in neurons. Here we show that mice heterozygous for the alpha2 isoform display increased anxiety-related behavior, reduced locomotor activity, and impaired spatial learning in the Morris water maze. Mice heterozygous for the alpha3 isoform displayed spatial learning and memory deficits unrelated to differences in cued learning in the Morris maze, increased locomotor activity, an increased locomotor response to methamphetamine, and a 40% reduction in hippocampal NMDA receptor expression. In contrast, heterozygous alpha1 isoform mice showed increased locomotor response to methamphetamine and increased basal and stimulated corticosterone in plasma. The learning and memory deficits observed in the alpha2 and alpha3 heterozygous mice reveal the Na,K-ATPase to be an important factor in the functioning of pathways associated with spatial learning. The neurobehavioral changes seen in heterozygous mice suggest that these mouse models may be useful in future investigations of the associated human CNS disorders.

Pubmed ID: 17234593


  • Moseley AE
  • Williams MT
  • Schaefer TL
  • Bohanan CS
  • Neumann JC
  • Behbehani MM
  • Vorhees CV
  • Lingrel JB


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

January 17, 2007

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA06733
  • Agency: NIDA NIH HHS, Id: DA14269
  • Agency: NHLBI NIH HHS, Id: HL28573
  • Agency: NHLBI NIH HHS, Id: HL66062

Mesh Terms

  • Animals
  • Anxiety
  • Isoenzymes
  • Maze Learning
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Motor Activity
  • Protein Subunits
  • Sodium-Potassium-Exchanging ATPase
  • Spatial Behavior