Involvement of the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 Isoform and Endogenous Cardiac Steroids in Depression- and Manic-like Behaviors
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<sup>+</sup>, K<sup>+</sup>-ATPase is a ma...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-01-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/25/3/1644 |
| Summary: | 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<sup>+</sup>, K<sup>+</sup>-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<sup>+</sup>, K<sup>+</sup>-ATPase are present in the brain. Previous studies have supported the involvement of the Na<sup>+</sup>, K<sup>+</sup>-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<sup>+/−</sup> 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<sup>+/−</sup> 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<sup>+</sup>, K<sup>+</sup>-ATPase activity in wt and α1<sup>+/−</sup> mice. The serum ECS was lower in α1<sup>+/−</sup> than wt mice. In addition, a study in human participants demonstrated that serum ECS significantly decreased after treatment. These results suggest that the Na<sup>+</sup>, K<sup>+</sup>-ATPase α1 isoform is involved in depressive- and manic-like behaviors and support that the Na<sup>+</sup>, K<sup>+</sup>-ATPase/ECS system participates in the etiology of BD. |
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| ISSN: | 1661-6596 1422-0067 |