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Proc Natl Acad Sci U S A. 2019 Jan 29;116(5):1770-1775. doi: 10.1073/pnas.1814335116. Epub 2019 Jan 14.

Transient receptor potential melastatin 2 governs stress-induced depressive-like behaviors.

Ko SY1,2, Wang SE1,2, Lee HK1,2, Jo S3, Han J4, Lee SH1,2, Choi M1,2, Jo HR1,2, Seo JY1,2, Jung SJ5,2,6, Son H5,2,7.

Author information

1
Graduate School of Biomedical Science and Engineering, Hanyang University, Seongdong-gu, Seoul 04763, Korea.
2
Hanyang Biomedical Research Institute, Hanyang University, Seongdong-gu, Seoul 04763, Korea.
3
Hanyang University Hospital for Rheumatic Diseases, Seongdong-gu, Seoul 04763, Korea.
4
Gencurix, Inc., Guro-gu, Seoul 08394, Korea.
5
Graduate School of Biomedical Science and Engineering, Hanyang University, Seongdong-gu, Seoul 04763, Korea; eurijj@hanyang.ac.kr hyeonson@hanyang.ac.kr.
6
Department of Physiology, College of Medicine, Hanyang University, Seongdong-gu, Seoul 04763, Korea.
7
Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seongdong-gu, Seoul 04763, Korea.

Abstract

Major depressive disorder (MDD) is a devastating disease that arises in a background of environmental risk factors, such as chronic stress, that produce reactive oxygen species (ROS) in the brain. The chronic stress-induced ROS production involves Ca2+ signals; however, the mechanism is poorly understood. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+-permeable cation channel that is highly expressed in the brain. Here we show that in animal models of chronic unpredictable stress (CUS), deletion of TRPM2 (Trpm2 -/- ) produces antidepressant-like behaviors in mice. This phenotype correlates with reduced ROS, ROS-induced calpain activation, and enhanced phosphorylation of two Cdk5 targets including synapsin 1 and histone deacetylase 5 that are linked to synaptic function and gene expression, respectively. Moreover, TRPM2 mRNA expression is increased in hippocampal tissue samples from patients with MDD. Our findings suggest that TRPM2 is a key agent in stress-induced depression and a possible target for treating depression.

KEYWORDS:

Cdk5; ROS; TRPM2; depression; neurogenesis

PMID:
30642955
PMCID:
PMC6358711
DOI:
10.1073/pnas.1814335116
[Indexed for MEDLINE]
Free PMC Article

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