The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids.
Many of the behavioral consequences of stress are mediated by the activation of the glucocorticoid receptor by stress-induced high levels of glucocorticoid hormones. To explore the molecular mechanisms of these effects, we combined in vivo and in vitro approaches. We analyzed mice carrying a brain-specific mutation (GR(NesCre)) in the glucocorticoid receptor gene (GR, also called Nr3c1) and cell lines that either express endogenous glucocorticoid receptor or carry a constitutively active form of the receptor (DeltaGR) that can be transiently induced. In the hippocampus of the wild-type [corrected] mice after stress, as well as in the cell lines, activation of glucocorticoid receptors greatly increased the expression and enzymatic activity of proteins in the MAPK signaling pathway and led to an increase in the levels of both Egr-1 mRNA and protein. In parallel, inhibition of the MAPK pathway within the hippocampus abolished the increase in contextual fear conditioning induced by glucocorticoids. The present results provide a molecular mechanism for the stress-related effects of glucocorticoids on fear memories.
Revest
Jean-Michel
JM
INSERM U588, Laboratoire de Physiopathologie du Comportement, Bordeaux Institute for Neurosciences, University Victor Segalen-Bordeaux 2, Domaine de Carreire, 146 Rue Léo Saignat, 33077 Bordeaux Cedex, France.
Di Blasi
Francesco
F
Kitchener
Pierre
P
Rougé-Pont
Françoise
F
Desmedt
Aline
A
Turiault
Marc
M
Tronche
François
F
Piazza
Pier Vincenzo
PV
D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000502:physiology; D005938:Glucocorticoids / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism* / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors