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.
Highlights
The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway is a linear kinase cascade with a well-understood biochemistry
Braficko/juvenile mutants spent significantly more time in the open arms of the EPM (Figure 1C; t[40] = 3.513; P,0.01), whereas no difference in the passive behavior in the forced swim test (FST) was observed (Figure 1D). These results indicate a normal depression-like behavior but decreased anxiety of adults upon Braf depletion in the juvenile brain. These results suggest a differential role of ERK/MAPK signaling for emotional behavior in the juvenile versus the adult brain
Conditional Braf knockout mice enabled us to unravel a new role of ERK/MAPK signaling for emotional behavior
Summary
The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway is a linear kinase cascade with a well-understood biochemistry. Cell surface receptors activate the small GTPase RAS, which itself activates Raf kinases. RAF phosphorylates and activates MEK1 and MEK2 that in turn phosphorylate and activate ERK1 and ERK2 kinases. Activated ERKs either translocate into the nucleus to phosphorylate transcription factors, or directly regulate cytoplasmic substrates. ERK/MAPK signaling is known as a key player in basic cellular processes like growth, differentiation, survival, and apoptosis. Among the three mammalian Raf isoforms, B-RAF is the strongest MEK-ERK activator expressed in neuronal tissues and testis [1] and was shown to be a protooncogene [2]. Other members of the ERK/MAPK signaling pathway cause the developmental RAS/MAPK or neuro-cardiofacial-cutaneous (NCFC) syndromes [3,4]
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