title: MAPK signaling determines anxiety in the juvenile mouse brain but depression-like behavior in adults.
abstract: MAP kinase signaling has been implicated in brain development, long-term memory, and the response to antidepressants. Inducible Braf knockout mice, which exhibit protein depletion in principle forebrain neurons, enabled us to unravel a new role of neuronal MAPK signaling for emotional behavior. Braf mice that were induced during adulthood showed normal anxiety but increased depression-like behavior, in accordance with pharmacological findings. In contrast, the inducible or constitutive inactivation of Braf in the juvenile brain leads to normal depression-like behavior but decreased anxiety in adults. In juvenile, constitutive mutants we found no alteration of GABAergic neurotransmission but reduced neuronal arborization in the dentate gyrus. Analysis of gene expression in the hippocampus revealed nine downregulated MAPK target genes that represent candidates to cause the mutant phenotype.Our results reveal the differential function of MAPK signaling in juvenile and adult life phases and emphasize the early postnatal period as critical for the determination of anxiety in adults. Moreover, these results validate inducible gene inactivation as a new valuable approach, allowing it to discriminate between gene function in the adult and the developing postnatal brain.
authors.affiliation: German Research Center for Environmental Health, Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Wefers
authors.forename: Christiane
authors.initials: C
authors.lastname: Hitz
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.forename: Dietrich
authors.initials: D
authors.lastname: Trümbach
authors.forename: Jens
authors.initials: J
authors.lastname: Hansen
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.forename: Benno
authors.initials: B
authors.lastname: Pütz
authors.forename: Jan M
authors.initials: JM
authors.lastname: Deussing
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Till
authors.initials: T
authors.lastname: Roenneberg
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Alcino
authors.initials: A
authors.lastname: Silva
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Ralf
authors.initials: R
authors.lastname: Kühn
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology* / Q000235:genetics; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D019295:Computational Biology; D003863:Depression / Q000209:etiology* / Q000235:genetics; D004644:Emotions; D005260:Female; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011963:Receptors, GABA-A / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D011963:Receptors, GABA-A; D048493:Proto-Oncogene Proteins B-raf