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The Journal of Neuroscience, January 17, 2007, 27(3):616-626; doi:10.1523/JNEUROSCI.4464-06.2007

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Behavioral/Systems/Cognitive
Deficiency in Na,K-ATPase Isoform Genes Alters Spatial Learning, Motor Activity, and Anxiety in Mice

Amy E. Moseley,^1 * Michael T. Williams,^2 * Tori L. Schaefer,² Cynthia S. Bohanan,¹ Jon C. Neumann,¹ Michael M. Behbehani,³ Charles V. Vorhees,² and Jerry B Lingrel¹

¹Department of Molecular Genetics, Biochemistry, and Microbiology, ²Division of Neurology, Department of Pediatrics, Cincinnati Children's Research Foundation, Cincinnati, Ohio 45229, and ³Department of Physiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267

Correspondence should be addressed to Dr. Jerry B Lingrel, University of Cincinnati, Department of Molecular Genetics, Biochemistry, and Microbiology, Cincinnati, OH 45267. Email: jerry.lingrel{at}uc.edu

Several disorders have been associated with mutations in Na,K-ATPase 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 1 isoform is found in many cell types, the 2 isoform is predominantly expressed in astrocytes, and the 3 isoform is exclusively expressed in neurons. Here we show that mice heterozygous for the 2 isoform display increased anxiety-related behavior, reduced locomotor activity, and impaired spatial learning in the Morris water maze. Mice heterozygous for the 3 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 1 isoform mice showed increased locomotor response to methamphetamine and increased basal and stimulated corticosterone in plasma. The learning and memory deficits observed in the 2 and 3 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.

Key words: knock-out mice; learning and memory; learning memory; Morris water maze; movement (motion, motor activity); Na,K- ATPase; NMDA receptor

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Received May 15, 2006; revised Dec. 8, 2006; accepted Dec. 8, 2006.

Correspondence should be addressed to Dr. Jerry B Lingrel, University of Cincinnati, Department of Molecular Genetics, Biochemistry, and Microbiology, Cincinnati, OH 45267. Email: jerry.lingrel{at}uc.edu

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