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      Phenotype Distinctions in Mice Deficient in the Neuron-Specific α3 Subunit of Na,K-ATPase: Atp1a3 tm1Ling/+ and Atp1a3 +/D801Y

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          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 ( Atp1a3 tm1Ling/+) 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 Atp1a3 tm1Ling/+ and Atp1a3 +/D801Y were different, and testing of each strain was tailored to its symptom range. Atp1a3 tm1Ling/+ 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.

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          Behavioral despair in mice: a primary screening test for antidepressants.

          A depressed state can be induced in mice by forcing them to swim in a narrow cylinder from which they cannot escape. After a brief period of vigorous activity the mice adopt a characteristic immobile posture which is readily identifiable. Immobility was reduced by tricyclic antidepressants, monoamine oxidase inhibitors and atypical antidepressants, as well as by electroconvulsive shock. Psychostimulants also reduced immobility but in contrast to antidepressants caused marked motor stimulation. Immobility was not affected by minor or major tranquilisers. These findings, closely parallel to those we have previously reported in rats, suggest that the procedure is selectively sensitive to antidepressant treatments. The mouse procedure is, however, more rapid and less costly than that with rats and is thus more suitable for the primary screening of antidepressant drugs.
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            Factors influencing behavior in the forced swim test.

            The forced swim test (FST) is a behavioral test in rodents which was developed in 1978 by Porsolt and colleagues as a model for predicting the clinical efficacy of antidepressant drugs. A modified version of the FST added the classification of active behaviors into swimming and climbing, in order to facilitate the differentiation between serotonergic and noradrenergic classes of antidepressant drugs. The FST is now widely used in basic research and the pharmaceutical screening of potential antidepressant treatments. It is also one of the most commonly used tests to assess depressive-like behavior in animal models. Despite the simplicity and sensitivity of the FST procedure, important differences even in baseline immobility rates have been reported between different groups, which complicate the comparison of results across studies. In spite of several methodological papers and reviews published on the FST, the need still exists for clarification of factors which can influence the procedure. While most recent reviews have focused on antidepressant effects observed with the FST, this one considers the methodological aspects of the procedure, aiming to summarize issues beyond antidepressant action in the FST. The previously published literature is analyzed for factors which are known to influence animal behavior in the FST. These include biological factors, such as strain, age, body weight, gender and individual differences between animals; influence of preconditioning before the FST: handling, social isolation or enriched environment, food manipulations, various kinds of stress, endocrine manipulations and surgery; schedule and routes of treatment, dosage and type of the drugs as well as experimental design and laboratory environmental effects. Consideration of these factors in planning experiments may result in more consistent FST results. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Immunofluorescent localization of three Na,K-ATPase isozymes in the rat central nervous system: both neurons and glia can express more than one Na,K-ATPase.

              In the CNS, there are multiple isozymes of the sodium and potassium ion-stimulated adenosine triphosphatase (Na,K-ATPase) that have differences in affinity for Na+, ATP, and cardiac glycosides. Three forms of the catalytic subunit (designated alpha 1, alpha 2, and alpha 3) are known to be derived from different genes, but little is known of the cellular distributions of the proteins or their physiological roles. Isozyme-specific monoclonal antibodies permitted the immunofluorescent localization of the 3 Na,K-ATPases in the rat CNS, and markedly different patterns of staining were seen. All 3 isozymes were detected, singly or in combination, in 1 or more neuronal structures, while both alpha 1 and alpha 2 were detected in glia. Many different neuroanatomic structures or cell types stained for more than 1 isozyme. Even when a structure or region stained for more than 1 isozyme, the pattern of staining was frequently dissimilar, suggesting complex differences in gene expression and cellular localization.
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                Author and article information

                Journal
                eNeuro
                eNeuro
                eneuro
                eNeuro
                eNeuro
                Society for Neuroscience
                2373-2822
                7 August 2024
                20 August 2024
                August 2024
                : 11
                : 8
                : ENEURO.0101-24.2024
                Affiliations
                [1] 1Department of Neurosurgery, Massachusetts General Hospital , Boston, Massachusetts 02114
                [2] 2Harvard Medical School , Boston, Massachusetts 02115
                [3] 3Department Anesthesia, Massachusetts General Hospital , Boston, Massachusetts 02114
                [4] 4The Jackson Laboratory , Bar Harbor, Maine 04609
                [5] 5Department of Ophthalmology, Massachusetts Eye and Ear Infirmary/Schepens Eye Research Institute, Harvard Medical School , Boston, Massachusetts 02114
                [6] 6Department of Biomedicine, Aarhus University , Aarhus 8000, Denmark
                [7] 7Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York 14203
                [8] 8Department of Neurology, University of California Davis School of Medicine , Sacramento, California 95817
                Author notes

                The authors declare no competing financial interests.

                Author contributions: C.M.L., A.B., and K.J.S. designed research; Y.B.L., A.N.S., M.V.S., T.C.J., and K.J.S. performed research; K.L.-H. contributed unpublished reagents/analytic tools; Y.B.L., E.A., A.N.S., M.V.S., C.M.L., M.T., N.M., T.C.J., E.N., and K.J.S. analyzed data; E.N. and K.J.S. wrote the paper.

                This work was supported by National Institutes of Health grants R01 NS058949, PI A.B.; R21 NS081558, PI K.J.S.; a grant from the Chan-Zuckerberg Initiative, PI David Liu; a grant from Hope for Annabel Foundation, PI K.J.S.; and a grant from Cure AHC Foundation, PI K.J.S.

                Correspondence should be addressed to Kathleen J. Sweadner at ksweadner@ 123456mgh.harvard.edu .
                Author information
                https://orcid.org/0000-0002-2817-5262
                Article
                eneuro-11-ENEURO.0101-24.2024
                10.1523/ENEURO.0101-24.2024
                11360364
                39111836
                2489f224-f5e0-482e-ba36-8c888f0eb87b
                Copyright © 2024 Liu et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 8 March 2024
                : 24 July 2024
                : 25 July 2024
                Funding
                Funded by: NIH , doi 10.13039/100000002;
                Award ID: NS081558
                Award ID: NS058949
                Funded by: CureAHC Foundation
                Funded by: Hope for Annabel
                Funded by: Chan-Zuckerberg Initative
                Categories
                3
                Research Article: New Research
                Disorders of the Nervous System
                Custom metadata
                August 2024

                atp1a3,disease mutation,motor testing,mouse model,na,k-atpase

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