2. Academic Validation
  3. CIP2A deficiency promotes depression-like behaviors in mice through inhibition of dendritic arborization

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

  • EMBO Rep. 2022 Oct 28;e54911. doi: 10.15252/embr.202254911.
Wen-Ting Hu # 1 2,  Zhen-Yu Liuyang # 1 3,  Yuan Tian 4,  Jia-Wei Liang 1,  Xiao-Lin Zhang 1,  Hui-Liang Zhang 1,  Guan Wang 4,  Yuda Huo 4,  Yang-Ping Shentu 5,  Jian-Zhi Wang 1,  Xiao-Chuan Wang 1,  You-Ming Lu 1 6,  Jukka Westermarck 7 8 9,  Heng-Ye Man 4,  Rong Liu 1 6 10
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China.
  • 3 Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 4 Department of Biology, Boston University, Boston, USA.
  • 5 Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 6 The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
  • 7 Turku Bioscience Centre, University of Turku, Turku, Finland.
  • 8 Åbo Akademi University, Turku, Finland.
  • 9 Institute of Biomedicine, University of Turku, Turku, Finland.
  • 10 Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • # Contributed equally.
PMID: 36305233 DOI: 10.15252/embr.202254911
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.

Keywords

AKT; CIP2A; PP2A; dendritic arborization; depression.

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