Protein synthesis at synaptic sites on dendrites

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, United States
Annual Review of Neuroscience (Impact Factor: 19.32). 02/2001; 24(1):299-325. DOI: 10.1146/annurev.neuro.24.1.299
Source: PubMed

ABSTRACT

Studies over the past 20 years have revealed that gene expression in neurons is carried out by a distributed network of translational machinery. One component of this network is localized in dendrites, where polyribosomes and associated membranous elements are positioned beneath synapses and translate a particular population of dendritic mRNAs. The localization of translation machinery and mRNAs at synapses endows individual synapses with the capability to independently control synaptic strength through the local synthesis of proteins. The present review discusses recent studies linking synaptic plasticity to dendritic protein synthesis and mRNA trafficking and considers how these processes are regulated. We summarize recent information about how synaptic signaling is coupled to local translation and to the delivery of newly transcribed mRNAs to activated synaptic sites and how local translation may play a role in activity-dependent synaptic modification.

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    • "Classic examples that illustrate the importance of local translational regulation in polarized eukaryotic cells include the translation at the cell periphery of fibroblasts during migration, within axonal growth cones of Xenopus retinal ganglion cells during axon guidance, and in the dendritic compartment of primary hippocampal neurons in synaptic plasticity (Jung et al., 2014). The latter has gained significant attention as the local production of synaptic proteins posits an elegant mechanism to explain how individual dendritic branches or even single synapses are modified locally in response to local stimulation (Steward and Schuman, 2001). Indeed, local translation within dendrites appears to be required for at least some forms of synaptic plasticity, particularly BDNF-mediated synaptic facilitation and mGluR-dependent long-term depression (Huber et al., 2000; Kang and Schuman, 1996). "
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    ABSTRACT: The vast majority of the mammalian genome is transcribed, generating a wealth of transcripts that do not have protein-coding potential. These non-coding RNAs (ncRNAs) have emerged as major mediators of compartmentalized gene expression with many important regulatory functions, and are therefore at the focus of biological research in many cellular systems. The expression of ncRNAs is particularly multifaceted in neurons, as they seem to be expressed in a highly cell-type and activity-dependent manner. Specific subclasses of ncRNAs, especially microRNAs (miRNAs), were implicated in the local regulation of mRNA translation in neuronal dendrites, a process of compartmentalized gene expression that is engaged during synaptic plasticity. Recent discoveries point towards a widespread involvement of ncRNA families in local translation, including less abundant small RNAs (PIWI-interacting RNAs (piRNAs), endogenous small interfering RNAs (endo-siRNAs)) and long ncRNAs (circular RNAs (circRNAs), long intergenic ncRNAs (lincRNAs)). The mechanisms underlying the dendritic transport and the regulatory function of ncRNAs in response to neuronal activity are being elucidated. The emerging picture is an intricate crosstalk between different ncRNA families, mRNAs and RNA-binding proteins (RBPs) that synergistically fine-tune the local dendritic proteome in an activity-dependent manner. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Full-text · Article · Jun 2015 · European journal of cell biology
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    • "Chain et al., 1999) developed a scenario that presumes that degradation frees protein synthesis from its endogenous presynaptic and postsynaptic 'negative' suppressor proteins, a widely held hypothesis (Willeumier et al., 2006; Mabb and Ehlers, 2010; Fioravante and Byrne, 2011; Khoutorsky et al., 2013), and thereby unmasks the action of the positive proteins (see also Dong et al., 2014; Wang et al., 2014). The possible roles for the newly synthesized proteins include replacing degraded proteins, increasing the levels of existing proteins, or expressing novel forms of proteins (Steward and Schuman, 2001). On the contrary, protein turnover is activity dependent in the sense that the activity can either suppress or increase the turnover of some kinds of proteins in dendritic spines (e.g., actin: Star et al., 2002 and spectrin: Vanderklish et al., 1995) via, for example, a cytosolic Ca 2+ -mediated truncation by proteases (Vanderklish et al., 1995, 2000; Bi et al., 1998; Ehlers, 2000, 2003). "
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    ABSTRACT: Long-term potentiation (LTP) remains the most widely accepted model for learning and memory. In accordance with this belief, the temporal differentiation of LTP into early and late phases is accepted as reflecting the differentiation of short-term and long-term memory. Moreover, during the past 30 years, protein synthesis inhibitors have been used to separate the early, protein synthesis-independent (E-LTP) phase and the late, protein synthesis-dependent (L-LTP) phase. However, the role of these proteins has not been formally identified. Additionally, several reports failed to show an effect of protein synthesis inhibitors on LTP. In this review, a detailed analysis of extensive behavioral and electrophysiological data reveals that the presumed correspondence of LTP temporal phases to memory phases is neither experimentally nor theoretically consistent. Moreover, an overview of the time courses of E-LTP in hippocampal slices reveals a wide variability ranging from <1 h to more than 5 h. The existence of all these conflictual findings should lead to a new vision of LTP. We believe that the E-LTP vs. L-LTP distinction, established with protein synthesis inhibitor studies, reflects a false dichotomy. We suggest that the duration of LTP and its dependency on protein synthesis are related to the availability of a set of proteins at synapses and not to the de novo synthesis of plasticity-related proteins. This availability is determined by protein turnover kinetics, which is regulated by previous and ongoing electrical activities and by energy store availability.
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    • "mRNAs packaged in RNA granules are transported close to synapses in a translationaly silent state (Krichevsky and Kosik 2001; Mayford et al. 1996; Wang et al. 2010a). Upon LTP induction, polyribosomes and local translation machinery at spine necks are activated to translate these locally targeted mRNAs (Kelleher et al. 2004b; Ostroff et al. 2002; Steward and Schuman 2001). As a tag, PKA interacts with PRPs by regulating the production and function of PRPs. "
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    ABSTRACT: Synaptic tagging and capture (STC) hypothesis has been receiving increasing attention because it refl ects heterosynaptic association of information processing during memory formation in the brain. Indeed, electrophysiological and behavioral studies suggest that STC is a better cellular model for memory formation than the conventional homosynaptic experiment. In STC, a short-lasting potentiation in one pathway becomes persistent when it is paired with a long-lasting potentiation in the other independent pathway. It has been proposed that the setting of synapse-specific tag and capture of non-synapse-specific diffusible gene products by the tag determines the fate of each pathway. However, the mechanism of STC is still elusive and three major questions should be answered: (1) What is the tag and how does it modulate synapse-specific plasticity? (2) How does the tag capture gene products? (3) What are the gene products and how are they produced? Although several molecules and processes have been suggested to answer to these questions, they only provide partial explanations about the phenomenon. Here, this article will discuss how PKA modulates synapse-specifi c neuronal processing by coordinating signaling molecules and processes through PKA anchoring proteins, and how anchored PKA is involved in the generation and capture of plasticity-related gene products. Having PKA as a key molecule, the goal of this article is to provide a unified model of STC that addresses the key questions.
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