ReviewLocal protein synthesis and its role in synapse-specific plasticity
Introduction
Recent studies in a variety of cell types have provided increasing evidence that the localization of mRNAs to distinct subcellular compartments serves as an important mechanism for regulating gene expression [1]. Regulated translation of localized mRNAs decentralizes the control of gene expression and shifts part of the control from the nucleus to distinct subcellular compartments, allowing the macromolecular composition of a specific compartment in a cell to be altered rapidly. This form of decentralization may prove to be particularly important in neurons, which are unique among cells in their extreme functional and morphological polarity, with each of the potentially thousands of presynaptic terminal boutons and postsynaptic spines made by a single neuron capable of operating as an autonomous compartment. There is strong evidence that the ability of these synaptic terminals to change the strength of their connections with experience is a cellular mechanism underlying learning and memory [2], [3]. Like memory, synaptic plasticity occurs in both short- and long-lasting forms. Unlike the short-term forms, the long-lasting forms require the synthesis of new mRNA and protein [4], [5]. A number of models have been postulated to explain how long-lasting, transcription-dependent forms of synaptic plasticity can occur in a synapse-specific manner [6], [7], [8], [9]. According to one model, the products of gene expression are delivered throughout the cell, but only function to increase synaptic strength at a synapse that has been ‘tagged’, in a protein-synthesis-independent manner, by synaptic activity. According to a second model, synaptic stimulation alters the targeting of molecules—either RNA or protein—from the cell soma to the stimulated synapse. A third model involves the local translation of dendritically localized mRNAs. By spatially restricting gene expression, RNA localization and regulated translation provide a means whereby transcription-dependent changes can rapidly occur in a synapse-specific manner. In this review we will discuss studies demonstrating a role for RNA localization and local protein synthesis during long-lasting forms of synaptic plasticity in neurons. To place the studies of neurons into a larger cell-biological context, we will also discuss studies from non-neuronal cells in which the mechanisms underlying RNA localization and regulated translation have been characterized, as well as studies indicating that many of these mechanisms may be used in neuronal cells as well.
Section snippets
A brief history of the discovery of mRNA in dendrites
The initial indication that translation might occur in compartments other than the cell body came from the discovery by Steward and Levy in 1982 of synapse-associated polyribosome complexes (SPRCs): clusters of polyribosomes and associated membranous cisterns selectively localized in distal processes beneath postsynaptic sites on the dendrites of central nervous system (CNS) granule cell neurons [10]. SPRCs were subsequently confirmed by numerous other investigators, giving empirical support to
Local protein synthesis in neuronal processes
A number of approaches have demonstrated that dendritic protein synthesis occurs. Biochemical and mechanical fractionation has been used to enrich samples for synaptic compartments, and metabolic labeling experiments have revealed that these fractions are capable of synthesizing proteins [21], [22]. A foreign mRNA was microinjected into dissected neurites of Lymnaea neurons and found to be translated [23]. In some studies, this extra-somatic translation was found to be regulated. For example,
Functions for local protein synthesis
A requirement for dendritic protein synthesis during neurotrophin-induced forms of long-term potentiation of rodent hippocampal Schaeffer collateral synapses was demonstrated by Kang and Schuman [25], who found that brief applications of neurotrophins to hippocampal slices produced a long-lasting potentiation that had a very rapid dependence on protein synthesis. This translation-dependent form of plasticity persisted even after the cell body layers of the pyramidal cells in area CA3 and CA1
How is mRNA localized to specific sites in non-neuronal cells?
The mechanisms underlying RNA localization have been well studied in non-neuronal cells [1], [32]. In Drosophila oocytes, localization of the morphogen bicoid to the anterior pole depends on cis-acting sequences in the 3′ untranslated region (UTR), which bind to a trans-acting protein called Staufen. Staufen-mediated localization of bicoid involves large RNA granules that are transported along the microtubule network. In a similar fashion, localization of the transforming growth factor Vg1 to
How is mRNA targeted to neuronal dendrites?
Similar mechanisms to those described above are beginning to be described in neurons. Mayford et al. [35] have found that the dendritic localization of CaMKIIα (Ca2+/calmodulin-dependent protein kinase IIα) depends on signals in the 3′UTR. When fused to β-galactoside mRNA, the 3′UTR of CaMKIIα is sufficient to mediate dendritic localization of this mRNA. Miller and Mayford [36] have recently introduced a CaMKIIα transgene lacking the 3′UTR into CaMKIIα-null mice. These mice completely lack
In neurons, targeting to dendrites can be regulated by mechanisms that operate at both the 3′ and 5′ end of the mRNA
To function as a mechanism of spatially regulating gene expression, mRNA localization must be accompanied by regulated translation of that mRNA. An understanding of some of the molecular mechanisms underlying translational regulation of dendritically localized mRNAs is beginning to emerge. Translation of one of the most abundant dendritically localized mRNAs in the rodent hippocampus, that encoding CaMKIIα, increases specifically in the dendritic compartment following tetanic stimulation [48]
Conclusions
In summary, abundant evidence indicates that local protein synthesis occurs in neurites and dendrites, that it is essential for some forms of synaptic plasticity, and that it is at least partially regulated by neurotransmitters. Only a subset of mRNAs are localized to the synaptic compartments, and some additional mRNAs are transported specifically in response to synaptic stimulation. Localization and translational control of synaptic mRNAs seems to depend upon mechanisms shared with other
Update
In a recent study, Christophe Schuster and colleagues [59] provide evidence that postsynaptic translational regulation also plays a role in long-lasting plasticity at the neuromuscular junction, with the local translation occurring subsynaptically in the larval muscle. The authors first show that components of the translational machinery and polyribosomes are associated with the subsynaptic reticulum of Drosophila larval neuromuscular junctions. They then use a variety of genetic manipulations
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
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