Staufen 2 regulates mGluR long-term depression and Map1b mRNA distribution in hippocampal neurons

Lebeau, Geneviève; Miller, Linda C.; Tartas, Maylis; McAdam, Robyn; Laplante, Isabel; Badeaux, Frédérique; DesGroseillers, Luc; Sossin, Wayne S.; Lacaille, Jean‐Claude

doi:10.1101/lm.2100611

Cited by 64 publications

(60 citation statements)

References 65 publications

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“…There are, however, exceptions; protein synthesis-dependent LTP at the connection between the entorhinal cortex and the dentate gyrus (the circuit where LTP was first observed) is insensitive to rapamycin (Panja et al 2009). Metabotropic receptor-mediated long-term depression (mGluR-LTD), another model of synaptic plasticity in CA1 rodent neurons, has also been reported to be sensitive to rapamycin by several groups (Hou and Klann 2004;Sharma et al 2010;Lebeau et al 2011;Bozdagi et al 2012). However, despite similar protocols used, not all laboratories have reported rapamycin sensitivity in mGluR-LTD (Auerbach et al 2011).…”

Section: Mtorc1 Synaptic Plasticity and Memorymentioning

confidence: 99%

A recollection of mTOR signaling in learning and memory

2013

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Mechanistic target of rapamcyin (mTOR) is a central player in cell growth throughout the organism. However, mTOR takes on an additional, more specialized role in the developed neuron, where it regulates the protein synthesis-dependent, plastic changes underlying learning and memory. mTOR is sequestered in two multiprotein complexes (mTORC1 and mTORC2) that have different substrate specificities, thus allowing for distinct functions at synapses. We will examine how learning activates the mTOR complexes, survey the critical effectors of this pathway in the context of synaptic plasticity, and assess whether mTOR plays an instructive or permissive role in generating molecular memory traces.

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Section: Mtorc1 Synaptic Plasticity and Memorymentioning

confidence: 99%

A recollection of mTOR signaling in learning and memory

2013

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“…Staufen2 is mainly expressed in the brain and is necessary for the microtubule-dependent delivery of CaMKIIa mRNA to dendrites (Jeong et al, 2007). Staufen1 is required for the late phase of long-term potentiation (L-LTP) in the hippocampus (Lebeau et al, 2008) whereas Staufen2 regulates mGluR-dependent long-term depression (mGluR-LTD) (Lebeau et al, 2011), suggesting distinct roles for the two Staufen proteins at the synapse.…”

Section: Trans-acting Factorsmentioning

confidence: 99%

BDNF-induced local protein synthesis and synaptic plasticity

2014

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a b s t r a c tBrain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and longterm potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-g (PLC-g) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre-and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short-and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation.This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

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“…We have previously proposed the concept of a neuronal RNA granule as a stalled polyribosome (10,11). Ribosomal stalling has been shown to occur in lysates from a mouse neuroblastoma cell line and in an in vitro rabbit reticulocyte lysate translation assay programmed with brain homogenate (12).…”

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Reactivation of stalled polyribosomes in synaptic plasticity

Graber

Hébert-Seropian

Khoutorsky

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Some forms of synaptic plasticity require rapid, local activation of protein synthesis. Although this is thought to reflect recruitment of mRNAs to free ribosomes, this would limit the speed and magnitude of translational activation. Here we provide compelling in situ evidence supporting an alternative model in which synaptic mRNAs are transported as stably paused polyribosomes. Remarkably, we show that metabotropic glutamate receptor activation allows the synthesis of proteins that lead to a functional long-term depression phenotype even when translation initiation has been greatly reduced. Thus, neurons evolved a unique mechanism to swiftly translate synaptic mRNAs into functional protein upon synaptic signaling using stalled polyribosomes to bypass the ratelimiting step of translation initiation. Because dysregulated plasticity is implicated in neurodevelopmental and psychiatric disorders such as fragile X syndrome, this work uncovers a unique translational target for therapies.M ost studies of translational control focus on initiation, the process where mRNAs recruit ribosomes and catalyze the first step of translation (1). This highly regulated and normally rate-limiting step of translation is followed by elongation and termination, resulting in completed proteins. Although multiple ribosomes on a given mRNA (a polyribosome) imply active peptide synthesis, we and others identified neuronal RNA granulesmotile aggregates of nontranslating ribosomes (2, 3). These electron-dense bodies contain single copies of synaptic mRNAs that are translationally silenced during their transport from soma to synapse (1, 4).Many models assume that neuronally transported mRNAs are translationally paused before completion of the initiation step of translation during transport. An appropriate synaptic signal would then activate translation (initiation/elongation/termination) of the granule mRNA. However, it is not clear how many free ribosomal subunits are present at synapses to support translation initiation. Further, at a typical translation elongation rate of six amino acids per s (5, 6), synthesis of larger synaptic proteins (e.g., microtubule-associated protein 1b; MAP1b) would take over 5 min even if initiation were immediate. These two factors constrain the speed and magnitude of synaptic translation and, thus, plasticity. As some forms of synaptic plasticity require rapid (<10 min) and localized activation of protein synthesis, an alternative model is wanting (7-9).We have previously proposed the concept of a neuronal RNA granule as a stalled polyribosome (10, 11). Ribosomal stalling has been shown to occur in lysates from a mouse neuroblastoma cell line and in an in vitro rabbit reticulocyte lysate translation assay programmed with brain homogenate (12). Whether neuronal ribosome stalling occurs in vivo is uncertain. We hypothesized that neuronal RNA granules contain paused ribosomes with incomplete proteins initiated in the soma before their packaging and transport to dendrites, where translation can be rapidly and loca...

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Staufen 2 regulates mGluR long-term depression and Map1b mRNA distribution in hippocampal neurons

Cited by 64 publications

References 65 publications

A recollection of mTOR signaling in learning and memory

A recollection of mTOR signaling in learning and memory

BDNF-induced local protein synthesis and synaptic plasticity

Reactivation of stalled polyribosomes in synaptic plasticity

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