Chen AP, Ohno M, Giese KP, Kuhn R, Chen RL, Silva AJ.. Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory. J Neurosci Res 83: 28-38

Department of Neurobiology, Brain Research Institute, University of California, Los Angeles, 90095-1761, USA.
Journal of Neuroscience Research (Impact Factor: 2.59). 01/2006; 83(1):28-38. DOI: 10.1002/jnr.20703
Source: PubMed


Raf kinases are downstream effectors of Ras and upstream activators of the MEK-ERK cascade. Ras and MEK-ERK signaling play roles in learning and memory (L&M) and neural plasticity, but the roles of Raf kinases in L&M and plasticity are unclear. Among Raf isoforms, B-raf is preferentially expressed in the brain. To determine whether B-raf has a role in synaptic plasticity and L&M, we used the Cre-LoxP gene targeting system to derive forebrain excitatory neuron B-raf knockout mice. This conditional knockout resulted in deficits in ERK activation and hippocampal long-term potentiation (LTP) and impairments in hippocampus-dependent L&M, including spatial learning and contextual discrimination. Despite the widespread expression of B-raf, this mutation did not disrupt other forms of L&M, such as cued fear conditioning and conditioned taste aversion. Our findings demonstrate that B-raf plays a role in hippocampal ERK activation, synaptic plasticity, and L&M.

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    • "Furthermore, the essential role of BRaf for oligodendrocyte maturation and myelination during postnatal central nervous system development was demonstrated [26]. In addition, BRaf is involved in synaptic plasticity, because Cre-mediated conditional elimination of BRaf in neurons expressing calcium/calmodulin-dependent protein kinase II alpha showed impaired hippocampal learning and memory [27]. "
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    ABSTRACT: This study focuses on the role of the kinase BRaf in postnatal brain development. Mice expressing truncated, non-functional BRaf in neural stem cell-derived brain tissue demonstrate alterations in the cerebellum, with decreased sizes and fuzzy borders of the glomeruli in the granule cell layer. In addition we observed reduced numbers and misplaced ectopic Purkinje cells that showed an altered structure of their dendritic arborizations in the hippocampus, while the overall cornus ammonis architecture appeared to be unchanged. In male mice lacking BRaf in the hippocampus the size of the granule cell layer was normal at postnatal day 12 (P12) but diminished at P21, as compared to control littermates. This defect was caused by a reduced ability of dentate gyrus progenitor cells to differentiate into NeuN positive granule cell neurons. In vitro cell culture of P0/P1 hippocampal cells revealed that BRaf deficient cells were impaired in their ability to form microtubule-associated protein 2 positive neurons. Together with the alterations in behaviour, such as autoaggression and loss of balance fitness, these observations indicate that in the absence of BRaf all neuronal cellular structures develop, but neuronal circuits in the cerebellum and hippocampus are partially disturbed besides impaired neuronal generation in both structures.
    PLoS ONE 03/2013; 8(3):e58259. DOI:10.1371/journal.pone.0058259 · 3.23 Impact Factor
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    • "However, conditional, brain-specific Braf knockout mice allow to investigate the role of ERK/MAPK signaling in the nervous system. Thereby it was shown, that Braf is essential for long-term potentiation, learning and memory, and synaptic plasticity [6]–[8]. Moreover, ERK/MAPK signaling was linked to neuronal differentiation, axonal growth [9], oligodendrocyte maturation [10], and is associated with autism [11] and the development of depression [12]. "
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    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.
    PLoS ONE 04/2012; 7(4):e35035. DOI:10.1371/journal.pone.0035035 · 3.23 Impact Factor
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    • "flox/flox mice do not show gross morphological abnormalities or reduced size compared to control littermates, and the expected Mendelian ratio of genotypes was observed suggesting no developmental defects in these mice (data not shown). Importantly , it has previously been shown that mice expressing Cre recombinase in the forebrain do not exhibit learning and memory deficits (Chen et al. 2006). We next characterized the p300 deletion pattern in p300 conditional knock-out mice. "
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    ABSTRACT: Histone acetylation plays a critical role during long-term memory formation. Several studies have demonstrated that the histone acetyltransferase (HAT) CBP is required during long-term memory formation, but the involvement of other HAT proteins has not been extensively investigated. The HATs CBP and p300 have at least 400 described interacting proteins including transcription factors known to play a role in long-term memory formation. Thus, CBP and p300 constitute likely candidates for transcriptional coactivators in memory formation. In this study, we took a loss-of-function approach to evaluate the role of p300 in long-term memory formation. We used conditional knock-out mice in which the deletion of p300 is restricted to the postnatal phase and to subregions of the forebrain. We found that p300 is required for the formation of long-term recognition memory and long-term contextual fear memory in the CA1 area of the hippocampus and cortical areas.
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