title: ERK-associated changes of AP-1 proteins during fear extinction.
abstract: Extensive research has unraveled the molecular basis of learning processes underlying contextual fear conditioning, but the mechanisms of fear extinction remain less known. Contextual fear extinction occurs when an aversive stimulus that initially caused fear is no longer present and depends on the activation of the extracellular signal-regulated kinase (ERK), among other molecules. Here we investigated how ERK signaling triggered by extinction affects its downstream targets belonging to the activator protein-1 (AP-1) transcription factor family. We found that extinction, when compared to conditioning of fear, markedly enhanced the interactions of active, phospho-ERK (pERK ) with c-Jun causing alterations of its phosphorylation state. The AP-1 binding of c-Jun was decreased whereas AP-1 binding of JunD, Jun dimerization protein 2 (JDP2) and ERK were significantly enhanced. The increased AP-1 binding of the inhibitory JunD and JDP2 transcription factors was paralleled by decreased levels of the AP-1 regulated proteins c-Fos and GluR2. These changes were specific for extinction and were MEK-dependent. Overall, fear extinction involves ERK/Jun interactions and a decrease of a subset of AP-1-regulated proteins that are typically required for fear conditioning. Facilitating the formation of inhibitory AP-1 complexes may thus facilitate the reduction of fear.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL 60611, USA.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Guedea
authors.forename: Christina
authors.initials: C
authors.lastname: Schrick
authors.forename: Yomayra F
authors.initials: YF
authors.lastname: Guzman
authors.forename: Katie
authors.initials: K
authors.lastname: Leaderbrand
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jovasevic
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Corcoran
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Tronson
authors.forename: Jelena
authors.initials: J
authors.lastname: Radulovic
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002070:Butadienes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005108:Extinction, Psychological / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007858:Learning / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009570:Nitriles / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018091:Receptors, AMPA; D018808:Transcription Factor AP-1; C113580:U 0126; C528955:junD protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C104722:glutamate receptor ionotropic, AMPA 2