| First Author | Holm TH | Year | 2016 |
| Journal | Sci Rep | Volume | 6 |
| Pages | 31972 | PubMed ID | 27549929 |
| Mgi Jnum | J:254463 | Mgi Id | MGI:6102714 |
| Doi | 10.1038/srep31972 | Citation | Holm TH, et al. (2016) Cognitive deficits caused by a disease-mutation in the alpha3 Na(+)/K(+)-ATPase isoform. Sci Rep 6:31972 |
| abstractText | 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 alpha3 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 alpha3 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 (alpha3(+/D801Y)) was generated. The alpha3(+/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 alpha3(+/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 alpha3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission. |
