CREB-pCREB-PER2 feedback loop mediates transition between mania and depression-like behaviors

Abstract

AbstractLittle is known about the mechanisms underlying the transition between mania and depression. We found here that ouabain decreased pCREB and PER2 levels in CA1 and induced mania-like behavior, which was attenuated by lithium and overexpression ofPer2in this region. Furthermore, knockdown ofPer2in CA1 induced mania-like behavior, in contrast, overexpression ofPer2resulted in depression-like behavior. Similar results were found in manipulations ofCreb1in CA1. Western blot analyses revealed that upregulations of CREB or PER2 can increase each other’s levels, besides pCREB, and vice versa. Therefore, the CREB– pCREB–PER2 pathway forms a positive feedback loop that mediates the transition between manic and depressive phenotypes.One-Sentence SummaryA novel molecular loop underlies phase inversion of bipolar disorder