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

Abstract

Little 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 of Per2 in this region. Furthermore, knockdown of Per2 in CA1 induced mania-like behavior, in contrast, overexpression of Per2 resulted in depression-like behavior. Similar results were found in manipulations of Creb1 in CA1. Western blot analyses revealed that upregulations of CREB or PER2 can increase each others 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