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

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.We thank Christopher W. Cowan and David S. Park for providing anti-HDAC5(Ser279) and anti-Prx2(Thr89), respectively. This work was supported by National Research Foundation of Korea Grants 2016R1A2B2006474 (to H.S.) and 2016R1A2B4013332 (to S.J.J.); Basic Science Research Program Grants 2017R1A6A3A01005765 (to S.E.W.) and 2017R1D1A1B03032858 (to M.C.); and Medical Research Center Grant 2017R1A5A2015395 (to H.S.) funded by the Ministry of Science and Technology, Republic of Korea