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

Abstract

Significance Transient receptor potential melastatin type 2 (TRPM2) is an oxidative stress-sensing calcium-permeable channel that is thought to contribute to the calcium influx associated with neurodegenerative diseases. Here we show that TRPM2 deficiency lowers chronic unpredictable stress (CUS)-induced reactive oxygen species (ROS) and calpain activation and prevents aberrant hyperactivation of cyclin-dependent kinase 5 (Cdk5). In mice models of CUS, genetic elimination of TRPM2 normalized behavioral deficits. Moreover, removal of Cdk5 reversed the antidepressant-like behaviors observed in Trpm2 −/− mice. Our results reveal the important roles of TRPM2 in raising ROS levels and aberrantly hyperactivating Cdk5 in mouse models of CUS and suggest that TRPM2 could be a target for treating ROS-induced neurodegenerative diseases such as depression.