Involvement of the Na+, K+-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors

Noa Horesh, Ilana Pelov, Ilana Pogodin, Hiba Zannadeh, Haim Rosen, Anastasiia Leonidovna Mikhrina, Moran Dvela-Levitt, Vishnu Priya Sampath, David Lichtstein

Research output: Contribution to journalArticlepeer-review


Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na+, K+-ATPase is a major plasma membrane transporter and signal transducer. The catalytic α subunit of this enzyme is the binding site for cardiac steroids. Three α isoforms of the Na+, K+-ATPase are present in the brain. Previous studies have supported the involvement of the Na+, K+-ATPase and endogenous cardiac steroids (ECS) in the etiology of BD. Decreased brain ECS has been found to elicit anti-manic and anti-depressive-like behaviors in mice and rats. However, the identity of the specific α isoform involved in these behavioral effects is unknown. Here, we demonstrated that decreasing ECS through intracerebroventricular (i.c.v.) administration of anti-ouabain antibodies (anti-Ou-Ab) decreased the activity of α1+/− mice in forced swimming tests but did not change the activity in wild type (wt) mice. This treatment also affected exploratory and anxiety behaviors in α1+/− but not wt mice, as measured in open field tests. The i.c.v. administration of anti-Ou-Ab decreased brain ECS and increased brain Na+, K+-ATPase activity in wt and α1+/− mice. The serum ECS was lower in α1+/− than wt mice. In addition, a study in human participants demonstrated that serum ECS significantly decreased after treatment. These results suggest that the Na+, K+-ATPase α1 isoform is involved in depressive- and manic-like behaviors and support that the Na+, K+-ATPase/ECS system participates in the etiology of BD.

Original languageEnglish
Article number1644
JournalInternational Journal of Molecular Sciences
Issue number3
StatePublished - 29 Jan 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.


This study was support in part by the Israel Science Foundation, Grants No. 2059/22 to DL.

FundersFunder number
Israel Science Foundation2059/22


    • Na, K-ATPase
    • bipolar disorder
    • endogenous cardiac steroids
    • forced swimming test
    • intracellular signaling
    • open field test
    • α isoform


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