CIP2A deficiency promotes depression-like behaviors in mice through inhibition of dendritic arborization

Wen-Ting Hu, Zhen-Yu Liuyang, Yuan Tian, Jia-Wei Liang, Xiao-Lin Zhang, Hui-Liang Zhang, Guan Wang, Yuda Huo, Yang-Ping Shentu, Jian-Zhi Wang, Xiao-Chuan Wang, You-Ming Lu, Jukka Westermarck, Heng-Ye Man, Rong Liu

Research output: Contribution to journalArticleScientificpeer-review

2 Citations (Scopus)
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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.

Original languageEnglish
Article numbere54911
Number of pages19
JournalEMBO Reports
Volume23
Issue number12
DOIs
Publication statusPublished - 6 Dec 2022
MoE publication typeA1 Journal article-refereed

Keywords

  • Humans
  • Mice
  • Animals
  • Depressive Disorder, Major/genetics
  • Phosphatidylinositol 3-Kinases
  • Neurons
  • Neuronal Plasticity

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