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Updated: Aug 23, 2025
Animal Models of Depression - Chronic Despair Model CDM
Published on: September 23, 2021
CIP2A deficiency promotes depression-like behaviors in mice through inhibition of dendritic arborization
Wen-Ting Hu1,2, Zhen-Yu Liuyang1,3, Yuan Tian4
1Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Major depressive disorder (MDD) is a severe mental illness. Decreased brain plasticity and dendritic fields have been consistently found in MDD patients and animal models; however, the underlying molecular mechanisms remain to be clarified. Here, we demonstrate that the deletion of cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor of protein phosphatase 2A (PP2A), leads to depression-like behaviors in mice. Hippocampal RNA sequencing analysis of CIP2A knockout mice shows alterations in the PI3K-AKT pathway and central nervous system development. In primary neurons, CIP2A stimulates AKT activity and promotes dendritic development. Further analysis reveals that the effect of CIP2A in promoting dendritic development is dependent on PP2A-AKT signaling. In vivo, CIP2A deficiency-induced depression-like behaviors and impaired dendritic arborization are rescued by AKT activation. Decreased CIP2A expression and impaired dendrite branching are observed in a mouse model of chronic unpredictable mild stress (CUMS). Indicative of clinical relevance to humans, CIP2A expression is found decreased in transcriptomes from MDD patients. In conclusion, we discover a novel mechanism that CIP2A deficiency promotes depression through the regulation of PP2A-AKT signaling and dendritic arborization.
Insights
Cancerous inhibitor of PP2A (CIP2A) deficiency causes depression-like behaviors in mice by impairing brain plasticity. Restoring AKT signaling in the brain may offer new therapeutic avenues for major depressive disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Major depressive disorder (MDD) is linked to reduced brain plasticity and dendritic fields.
- The molecular underpinnings of these changes in MDD remain incompletely understood.
Purpose of the Study:
- To investigate the role of cancerous inhibitor of PP2A (CIP2A) in depression.
- To elucidate the molecular mechanisms by which CIP2A influences brain plasticity and depressive behaviors.
Main Methods:
- Utilized CIP2A knockout mice to study depression-like behaviors and hippocampal gene expression.
- Performed primary neuron culture experiments to assess CIP2A's effect on AKT signaling and dendritic development.
- Employed a chronic unpredictable mild stress (CUMS) mouse model and analyzed human MDD patient transcriptomes.
Main Results:
- CIP2A deletion induced depression-like behaviors and impaired dendritic arborization in mice.
- CIP2A was found to stimulate AKT activity, promoting dendritic development via PP2A-AKT signaling.
- Depression-like behaviors and dendritic deficits in knockout mice were reversed by AKT activation.
- Reduced CIP2A expression and dendritic branching were observed in CUMS mice and human MDD patients.
Conclusions:
- CIP2A deficiency promotes depression by disrupting PP2A-AKT signaling and dendritic arborization.
- CIP2A plays a critical role in maintaining brain plasticity relevant to major depressive disorder.
- These findings reveal a novel molecular pathway implicated in MDD pathogenesis.
