Suppression of the MEK/ERK signaling pathway reverses depression-like behaviors of CRF2-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 (CRF1) and CRF receptor 2 (CRF2), located at multiple anatomical sites. Clinical data indicate that stress response dysfunctions, such as excessive CRF activity and hyperstimulation of CRF1, 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 CRF2 (CRF2-/-) display increased anxiety and depression-like behaviors. In this study, we found CRF2-/- 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 CRF1, 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 CRF2-/- mice. Similarly, treatment with [Glu(11,16)]Ast reversed depression phenotype of CRF2-/- 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 CRF1 activity, in the absence of CRF2, produces a depression-dominated phenotype through the activation of the MEK/ERK pathway.
Specialized Neuroscience Research Project 2, John A Burns School of Medicine, University of Hawaii, 651 Ilalo St Honolulu, HI 96813, USA. cedomir@hawaii.edu
Cedomir
C
Todorovic
Tessi
T
Sherrin
Matthew
M
Pitts
Cathrin
C
Hippel
Martin
M
Rayner
Joachim
J
Spiess
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003863:Depression / Q000378:metabolism* / Q000523:psychology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D000099052:CRF Receptor, Type 1
D002070:Butadienes; C101531:CRF receptor type 2; D004791:Enzyme Inhibitors; D009570:Nitriles; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; C113580:U 0126; C104416:astressin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases