RT Journal Article
SR Electronic
T1 Phenotype Distinctions in Mice Deficient in the Neuron-Specific α3 Subunit of Na,K-ATPase: <em>Atp1a</em>3<sup>tm1Ling/+</sup> and <em>Atp1a3</em><sup>+/D801Y</sup>
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0101-24.2024
DO 10.1523/ENEURO.0101-24.2024
VO 11
IS 8
A1 Liu, Yi Bessie
A1 Arystarkhova, Elena
A1 Sacino, Amanda N.
A1 Szabari, Margit V.
A1 Lutz, Cathleen M.
A1 Terrey, Markus
A1 Morsci, Natalia S.
A1 Jakobs, Tatjana C.
A1 Lykke-Hartmann, Karin
A1 Brashear, Allison
A1 Napoli, Elenora
A1 Sweadner, Kathleen J.
YR 2024
UL http://www.eneuro.org/content/11/8/ENEURO.0101-24.2024.abstract
AB ATP1A3 is a Na,K-ATPase gene expressed specifically in neurons in the brain. Human mutations are dominant and produce an unusually wide spectrum of neurological phenotypes, most notably rapid-onset dystonia parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Here we compared heterozygotes of two mouse lines, a line with little or no expression (Atp1a3tm1Ling/+) and a knock-in expressing p.Asp801Tyr (D801Y, Atp1a3+/D801Y). Both mouse lines had normal lifespans, but Atp1a3+/D801Y had mild perinatal mortality contrasting with D801N mice (Atp1a3+/D801N), which had high mortality. The phenotypes of Atp1a3tm1Ling/+ and Atp1a3+/D801Y were different, and testing of each strain was tailored to its symptom range. Atp1a3tm1Ling/+ mice displayed little at baseline, but repeated ethanol intoxication produced hyperkinetic motor abnormalities not seen in littermate controls. Atp1a3+/D801Y mice displayed robust phenotypes: hyperactivity, diminished posture consistent with hypotonia, and deficiencies in beam walk and wire hang tests. Symptoms also included qualitative motor abnormalities that are not well quantified by conventional tests. Paradoxically, Atp1a3+/D801Y showed sustained better performance than wild type on the accelerating rotarod. Atp1a3+/D801Y mice were overactive in forced swimming and afterward had intense shivering, transient dystonic postures, and delayed recovery. Remarkably, Atp1a3+/D801Y mice were refractory to ketamine anesthesia, which elicited hyperactivity and dyskinesia even at higher dose. Neither mouse line exhibited fixed dystonia (typical of RDP patients), spontaneous paroxysmal weakness (typical of AHC patients), or seizures but had consistent, measurable neurological abnormalities. A gradient of variation supports the importance of studying multiple Atp1a3 mutations in animal models to understand the roles of this gene in human disease.