Behavioral alterations in mice lacking the translation repressor 4E-BP2

Banko, Jessica L.; Merhav, Maayan; Stern, Elad; Sonenberg, Nahum; Rosenblum, Kobi; Klann, Eric

doi:10.1016/j.nlm.2006.08.012

Cited by 93 publications

(83 citation statements)

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“…The role of translational regulation in synaptic plasticity and memory consolidation is now under extensive investigation (Kelleher et al, 2004;Belelovsky et al, 2005;Banko et al, 2007;Costa-Mattioli et al, 2007). Translation can be modulated and controlled by mTOR, which regulates the synthesis of members of translation machinery.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, some of these correlative events between protein phosphorylation in the GC and taste learning are known to affect and modulate the function of the translation machinery (Belelovsky et al, 2005). In addition, the involvement of different translation initiation factors, including eIF2␣, 4E-BP2, and S6K, in taste learning was reported in transgenic mice studies (Banko et al, 2007;Costa-Mattioli et al, 2007;Antion et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Biphasic Activation of the mTOR Pathway in the Gustatory Cortex Is Correlated with and Necessary for Taste Learning

Belelovsky

Kaphzan²,

Elkobi³

et al. 2009

Journal of Neuroscience

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Different forms of memories and synaptic plasticity require synthesis of new proteins at the time of acquisition or immediately after. We are interested in the role of translation regulation in the cortex, the brain structure assumed to store long-term memories. The mammalian target of rapamycin, mTOR (also known as FRAP and RAFT-1), is part of a key signal transduction mechanism known to regulate translation of specific subset of mRNAs and to affect learning and synaptic plasticity. We report here that novel taste learning induces two waves of mTOR activation in the gustatory cortex. Interestingly, the first wave can be identified both in synaptoneurosomal and cellular fractions, whereas the second wave is detected in the cellular fraction but not in the synaptic one. Inhibition of mTOR, specifically in the gustatory cortex, has two effects. First, biochemically, it modulates several known downstream proteins that control translation and reduces the expression of postsynaptic density-95 in vivo. Second, behaviorally, it attenuates long-term taste memory. The results suggest that the mTOR pathway in the cortex modulates both translation factor activity and protein expression, to enable normal taste memory consolidation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biphasic Activation of the mTOR Pathway in the Gustatory Cortex Is Correlated with and Necessary for Taste Learning

Belelovsky

Kaphzan²,

Elkobi³

et al. 2009

Journal of Neuroscience

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“…4E-BP2 Ϫ/Ϫ mice show enhanced LTP when induced with a weak tetanic train, whereas L-LTP induced by four tetanic trains is impaired. Lack of 4E-BP2 not only alters LTP but also changes LTD because metabotropic glutamate receptor LTD is facilitated in these mice (45)(46)(47). A number of behavioral abnormalities in spatial memory, associative memory, fear conditioning, and even working memory were observed in mice deficient in 4E-BP2 (46,47).…”

Section: Mtor and Eif4f Complex In Synaptic Plasticity And Memorymentioning

confidence: 99%

“…Lack of 4E-BP2 not only alters LTP but also changes LTD because metabotropic glutamate receptor LTD is facilitated in these mice (45)(46)(47). A number of behavioral abnormalities in spatial memory, associative memory, fear conditioning, and even working memory were observed in mice deficient in 4E-BP2 (46,47). Although these studies demonstrate that 4E-BP2 is important for synaptic plasticity and memory, it is not clear whether 4E-BPs are the major mTORC1 downstream effectors in the brain.…”

Section: Mtor and Eif4f Complex In Synaptic Plasticity And Memorymentioning

confidence: 99%

Translational Control Mechanisms in Long-lasting Synaptic Plasticity and Memory

Gkogkas

Sonenberg

Costa-Mattioli

2010

Journal of Biological Chemistry

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“…Similar phenotypes have been observed in mice carrying a constitutively active mutant variant (Ser 52 to Ala) of eIF2␣ (17). Mice lacking eIF4E-binding protein 2 (4EBP2) exhibited increased cap-dependent translation and altered long-term potentiation, long-term depression (LTD), and learning (18,19). Mice expressing a transgene encoding a dominant-negative version of MEK, which inhibits the phosphorylation of eIF4E and protein synthesis, were found to have learning deficits (20).…”

mentioning

confidence: 99%

Brain-derived Neurotrophic Factor Enhances the Basal Rate of Protein Synthesis by Increasing Active Eukaryotic Elongation Factor 2 Levels and Promoting Translation Elongation in Cortical Neurons

Takei

Kawamura

Ishizuka

et al. 2009

Journal of Biological Chemistry

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The constitutive and activity-dependent components of protein synthesis are both critical for neural function. Although the mechanisms controlling extracellularly induced protein synthesis are becoming clear, less is understood about the molecular networks that regulate the basal translation rate. Here we describe the effects of chronic treatment with various neurotrophic factors and cytokines on the basal rate of protein synthesis in primary cortical neurons. Among the examined factors, brain-derived neurotrophic factor (BDNF) showed the strongest effect. The rate of protein synthesis increased in the cortical tissues of BDNF transgenic mice, whereas it decreased in BDNF knock-out mice. BDNF specifically increased the level of the active, unphosphorylated form of eukaryotic elongation factor 2 (eEF2). The levels of active eEF2 increased and decreased in BDNF transgenic and BDNF knock-out mice, respectively. BDNF decreased kinase activity and increased phosphatase activity against eEF2 in vitro. Additionally, BDNF shortened the ribosomal transit time, an index of translation elongation. In agreement with these results, overexpression of eEF2 enhanced protein synthesis. Taken together, our results demonstrate that the increased level of active eEF2 induced by chronic BDNF stimulation enhances translational elongation processes and increases the total rate of protein synthesis in neurons.The synthesis and post-translational modification of proteins play key roles in neural development, synaptic plasticity, and cognitive brain functions such as learning and memory (1, 2). Recent studies have revealed that activity-dependent regulation of translation affects neural plasticity (3, 4). Previously, we reported that BDNF, 2 a critical molecule for neural plasticity (5-7), enhances protein synthesis and activates the translational machinery in central nervous system neurons (8). In addition, neurotransmitters such as glutamate (9, 10), dopamine (11), and serotonin (12) are also reported to facilitate translation in neurons. These observations indicate that endogenous molecules can acutely modulate neuronal translation in response to neural activity. Translation of an mRNA molecule comprises three steps: initiation, elongation, and release (or termination) (13). In the first step, mRNA and methionyltRNA i Met are recruited to a ribosome. During elongation, aminoacyl-tRNAs are sequentially recruited and the nascent peptide chain lengthens incrementally as amino acids are covalently attached via peptide bonds. Finally, the polypeptide chain is released from the ribosome. Each step is regulated by a variety of factors. The activities of these regulatory proteins are predominantly controlled by phosphorylation and GTP binding. BDNF activates both initiation and elongation by modulating these processes (8,14,15).In addition to these acute, stimulation-induced changes in the translation rate, the long term regulation of translation plays important roles in developing and mature brains. In fact, recent studies have shown that ge...

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Behavioral alterations in mice lacking the translation repressor 4E-BP2

Cited by 93 publications

References 40 publications

Biphasic Activation of the mTOR Pathway in the Gustatory Cortex Is Correlated with and Necessary for Taste Learning

Biphasic Activation of the mTOR Pathway in the Gustatory Cortex Is Correlated with and Necessary for Taste Learning

Translational Control Mechanisms in Long-lasting Synaptic Plasticity and Memory

Brain-derived Neurotrophic Factor Enhances the Basal Rate of Protein Synthesis by Increasing Active Eukaryotic Elongation Factor 2 Levels and Promoting Translation Elongation in Cortical Neurons

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