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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 languageAmerican English
Article number1644
JournalInternational Journal of Molecular Sciences
Volume25
Issue number3
DOIs
StatePublished - 29 Jan 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Keywords

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

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