title: Cognitive deficits caused by a disease-mutation in the α3 Na(+)/K(+)-ATPase isoform.
abstract: The Na(+)/K(+)-ATPases maintain Na(+) and K(+) electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na(+)/K(+)-ATPase α3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC. Despite intensive research, mechanisms underlying these disorders remain largely unknown. To study the genotype-to-phenotype relationship, a heterozygous knock-in mouse harboring the D801Y mutation (α3(+/D801Y)) was generated. The α3(+/D801Y) mice displayed hyperactivity, increased sensitivity to chemically induced epileptic seizures and cognitive deficits. Interestingly, no change in the excitability of CA1 pyramidal neurons in the α3(+/D801Y) mice was observed. The cognitive deficits were rescued by administration of the benzodiazepine, clonazepam, a GABA positive allosteric modulator. Our findings reveal the functional significance of the Na(+)/K(+)-ATPase α3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission.
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.
authors.forename: Thomas Hellesøe
authors.initials: TH
authors.lastname: Holm
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.
authors.forename: Toke Jost
authors.initials: TJ
authors.lastname: Isaksen
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Glerup
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Heuck
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Bøttger
authors.affiliation: Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus, Denmark.
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Nedergaard
authors.affiliation: Stereology and Electron Microscopy Laboratory, Center for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Jens Randel
authors.initials: JR
authors.lastname: Nyengaard
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.
authors.forename: Mogens
authors.initials: M
authors.lastname: Andreasen
authors.affiliation: Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.|Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus, Denmark.|Danish Research Institute for Translational Neuroscience-DANDRITE, Nordic-EMBL Partnership of Molecular Medicine, Aarhus University, Department of Molecular Biology and Genetics and Department of Biomedicine, DK-8000 Aarhus C, Denmark.
authors.forename: Poul
authors.initials: P
authors.lastname: Nissen
authors.affiliation: Aarhus University, Department of Biomedicine, DK-8000 Aarhus, Denmark.|Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology and Genetics, DK-8000 Aarhus C, Denmark.|Aarhus Institute of Advanced Studies (AIAS), Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: Lykke-Hartmann
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D002460:Cell Line; D003072:Cognition Disorders / Q000235:genetics* / Q000523:psychology; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D008568:Memory; D051379:Mice; D009154:Mutation; D010641:Phenotype; D012640:Seizures / Q000139:chemically induced / Q000235:genetics*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D065853:Spatial Learning
chemical_list: C526097:Atp1a3 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase