Suppression of the MEK/ERK signaling pathway reverses depression-like behaviors of CRF(2)-deficient mice

The neuropeptide corticotropin-releasing factor (CRF) plays a critical role in the proper functioning of the stress response system through its actions on its receptors, CRF receptor 1 (CRF(1)) and CRF receptor 2 (CRF(2)), located at multiple anatomical sites. Clinical data indicate that stress response dysfunctions, such as excessive CRF activity and hyperstimulation of CRF(1), are present in a range of stress-related disorders, including depression and anxiety disorders. Our previous work along with that of other laboratories has demonstrated that mice deficient in CRF(2) (CRF(2)−/−) display increased anxiety and depression-like behaviors. In this study we found CRF(2)−/− mice display increased hippocampal levels of activated (phosphorylated) mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and ribosomal protein S6 kinases 1 (RSK1). These changes can be explained by overactive hippocampal CRF(1), in view of the finding that the application of the non-selective CRF receptor antagonist [Glu(11,16)] astressin ([Glu(11,16)]Ast) into the dorsal hippocampus of mutant mice returned the levels of the phosphorylated proteins to baseline. Moreover, inhibition of the hippocampal MEK/ERK pathway with the specific MEK inhibitor U0126, decreased depression-like behaviors in the forced swim test and tail suspension test of CRF(2)−/− mice. Similarly, treatment with [Glu(11,16)]Ast reversed depression phenotype of CRF(2)−/− mice without affecting the phenotype of wild-type littermates. Our results support an involvement of CRF receptors in the development of depression, such that elevated hippocampal CRF(1) activity, in the absence of CRF(2), produces a depression-dominated phenotype via activation of the MEK/ERK pathway.