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

Abstract

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 nonselective 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 through the activation of the MEK/ERK pathway. © 2009 Nature Publishing Group.