The crosstalk between CREB and PER2 mediates the transition between mania- and depression-like behavior.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by alternating manic and depressive episodes. The molecular mechanisms underlying the transition between mania and depression remain unclear. Utilizing a mania animal model induced by ouabain, we observed reduced phosphorylated level of cyclic AMP-responsive element-binding protein (pCREB) and Period (PER)2 expression in the cornu ammonis (CA1) region of the hippocampus, which were restored by lithium treatment. shRNA knockdown of CREB or Per2 in CA1 region induced mania-like behavior, while overexpression of both factors resulted in depression-like behavior. Furthermore, our protein analyses revealed that the upregulation or downregulation of CREB or Per2 influenced each other's expression. Co-immunoprecipitation results demonstrated that CREB interacts with PER2. Taken together, our data suggest for potential inter-regulatory crosstalk between CREB-PER2 in hippocampal CA1 region, which mediates the transition between mania- and depression-like behaviors.