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• W2072130720 abstract "Synapse formation is initiated by cell-cell contact between appropriate pre- and postsynaptic cells and is followed by recruitment of protein complexes in both pre- and postsynaptic compartments. In this issue of Neuron, Lyles et al. show that in cultured Aplysia neurons, clustering of an mRNA at nascent synapses is not only induced by the recognition between synaptic partners, but is also required for further synaptic development and maintenance. Synapse formation is initiated by cell-cell contact between appropriate pre- and postsynaptic cells and is followed by recruitment of protein complexes in both pre- and postsynaptic compartments. In this issue of Neuron, Lyles et al. show that in cultured Aplysia neurons, clustering of an mRNA at nascent synapses is not only induced by the recognition between synaptic partners, but is also required for further synaptic development and maintenance. Neurons are large, highly differentiated cells with complex morphologies. Synapses, the business ends of neurons, are frequently localized in distal neurites, far away from the cell body. How do distal neurites acquire and maintain the repertoire of proteins that are required for synaptic function? In many cases, passive diffusion is not fast enough to efficiently deliver proteins and organelles to synapses due to the great distance between the neuronal cell body and distal neurites. Two active mechanisms have been proposed to supply the distal compartments with their constituents. First, protein may be synthesized in the cell body and transported to distal neurites. A large family of molecular motors traffic cytosolic components and organelles back and forth between neurites and the cell body (Vale, 2003Vale R.D. Cell. 2003; 112: 467-480Abstract Full Text Full Text PDF PubMed Scopus (1512) Google Scholar). Alternatively, protein synthesis may take place locally in neurites. A growing body of evidence supports the notion that local translation in neurites is important for the development and plasticity of neural circuits. It is worth noting that local translation requires the presence of mRNA, ribosomes, and translational machinery at neurites, which is likely to depend on molecular motor-based intracellular trafficking. Classic experiments performed by Oswald Steward and colleagues showed that polyribosomes were selectively localized beneath postsynaptic sites in the dendrites of CNS neurons (Steward, 1983Steward O. Cold Spring Harb. Symp. Quant. Biol. 1983; 48: 745-759Crossref PubMed Google Scholar, Steward and Fass, 1983Steward O. Fass B. Prog. Brain Res. 1983; 58: 131-136Crossref PubMed Scopus (57) Google Scholar, Steward and Levy, 1982Steward O. Levy W.B. J. Neurosci. 1982; 2: 284-291Crossref PubMed Google Scholar). Later studies showed that both mRNA and translation machinery were present at dendritic spines (reviewed by Steward and Schuman, 2001Steward O. Schuman E.M. Annu. Rev. Neurosci. 2001; 24: 299-325Crossref PubMed Scopus (595) Google Scholar). The presence of particular transcripts in axonal growth cones and their importance in axon guidance have also been suggested (Brittis et al., 2002Brittis P.A. Lu Q. Flanagan J.G. Cell. 2002; 110: 223-235Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, Campbell and Holt, 2001Campbell D.S. Holt C.E. Neuron. 2001; 32: 1013-1026Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar). Still, many questions regarding mRNA localization and function at synapses have not been clearly addressed. For example, at what point in time does a particular mRNA localize to synapses during the course of synapse formation and maturation? What developmental events trigger this clustering at synapses? Is the increased concentration of mRNA at synapses due to redistribution of preexisting mRNA or due to new transcription? Finally, is synaptic mRNA required for synapse formation? In this study, Lyles et al., 2006Lyles V. Zhao Y. Martin K.C. Neuron. 2006; 49 (this issue): 349-356Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar presented an elegant set of experiments to address these questions while studying the neuropeptide sensorin. In culture, Aplysia neurons form functional synapses, whose activity can be readily measured with electrophysiology. Remarkably, synapse formation in vitro maintains target specificity found in intact animals, whereby isolated Aplysia sensory neurons preferentially form synapses onto the motor neurons that are their natural postsynaptic partners. These features, combined with the ability to perform RNA interference and in situ hybridization experiments, make cultured Aplysia neurons an ideal system for testing mRNA localization and function at synapses. The authors found sensorin transcript in a cDNA library from isolated processes of sensory neurons. Consistent with previous reports, they found that sensorin mRNA is localized in distal neurites (Brunet et al., 1991Brunet J.F. Shapiro E. Foster S.A. Kandel E.R. Iino Y. Science. 1991; 252: 856-859Crossref PubMed Scopus (77) Google Scholar). More specifically, they reported that sensorin mRNA is particularly concentrated at presynaptic sites. Furthermore, this clustering effect is most efficiently induced when the appropriate target neurons are cocultured, suggesting that recognition between synaptic partners triggers mRNA localization at synapses. Next, the authors analyzed the mechanism of sensorin mRNA localization by asking whether the clustering of mRNA is due to redistribution of existing mRNA or synthesis of new mRNA. Surprisingly, they found that a transcriptional inhibitor, actinomycin D, blocks synaptic accumulation of sensorin mRNA. This result implies that the synaptically localized sensorin mRNA is a new population of mRNA that is induced by synapse formation signals. It also suggests that there must be differences between the newly synthesized mRNA and the preexisting mRNA to aid the selective accumulation of new mRNA at synapses. Therefore, signals generated by nascent synapses must travel to the nucleus to stimulate the transcription of sensorin. The newly synthesized sensorin mRNA needs to carry a tag that enables it to be subsequently “trapped” by synapses. What is the function of the synaptically localized sensorin mRNA? Previous studies showed that sensorin is localized in axons and varicosities and can be released from sensory neurons when cocultured with appropriate synaptic targets (Hu et al., 2004Hu J.Y. Glickman L. Wu F. Schacher S. Neuron. 2004; 43: 373-385Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). An activity-neutralizing sensorin antibody was found to inhibit synapse formation, suggesting that sensorin plays an indispensable role in sensory-motor synapse formation in cultured Aplysia neurons (Hu et al., 2004Hu J.Y. Glickman L. Wu F. Schacher S. Neuron. 2004; 43: 373-385Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). To test the function of synaptically localized sensorin mRNA, the authors used dsRNA to knock down the level of sensorin message. Interestingly, they found that dsRNA treatment abolishes the enrichment of sensorin mRNA at synapses without affecting the level or synaptic localization of sensorin protein. The same dsRNA treatment also strongly inhibits synaptic strength. These data suggest that new translation of sensorin mRNA is required for synapse formation or maintenance, which also implies that sensorin protein is more stable than sensorin mRNA and that newly synthesized sensorin protein is different from the preexisting sensorin protein at synapses. Taken together, the experiments presented in this paper support the following model. During synapse formation, appropriate pre- and postsynaptic partners recognize each other and send certain signals to the nuclei of sensory neurons to stimulate the transcription of genes like sensorin (Figure 1). The newly synthesized mRNA carries tags that allow it to be targeted to nascent synapses. The synaptically localized mRNA is subsequently translated in the distal axon, which produces sensorin protein. Sensorin protein is restricted to synapses and potentially released by sensory neurons, which is essential for synapse formation or maintenance. This model raises several interesting points about synapse formation. First, synapse formation involves recruitment of not only proteins and organelles such as synaptic vesicles, but also mRNA. The fast dynamics of sensorin mRNA recruitment is suggestive of its importance during the early phase of synaptogenesis, which is further supported by the observation that the functional synaptic current depends on synaptically localized sensorin mRNA. Interestingly, appropriate postsynaptic partners trigger synaptic accumulation of mRNA in sensory neurons more efficiently than nontarget motor neurons. Experiments presented in this paper do not directly address the question of whether sensorin is involved in establishing synaptic target specificity, or whether it functions downstream of the specificity mechanisms to increase synaptic efficacy. In other words, is sensorin sufficient to override synaptic target specificity or sufficient to increase synaptic efficacy? A previous study showed that addition of sensorin protein to culture media increases both the EPSP amplitude and the number of varicosities when sensory neurons are cocultured with their appropriate synaptic targets (Hu et al., 2004Hu J.Y. Glickman L. Wu F. Schacher S. Neuron. 2004; 43: 373-385Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). It would be interesting to know whether the addition of sensorin would be sufficient to trigger synapse formation when sensory neurons are cocultured with inappropriate target motor neurons. Second, one of the intriguing discoveries presented here is that sensorin dsRNA treatment does not affect sensorin protein localization but does affect synapse formation, suggesting that local translation at synapses is essential for the function of sensorin. Why do neurons need additional translation at synapses when there is plenty of sensorin protein in the neurite already? The same question can be asked for other neuritically localized mRNAs such as CaMKII and β-actin. This manuscript presents exciting results that highlight the potential functional difference between the newly synthesized mRNA and sensorin protein compared with the existing mRNA and protein. These findings imply that posttranscriptional and posttranslational modifications may be used to tag mRNA and protein, which then alters the localization and biological function of sensorin. It is conceivable that the turnover of such tags can serve as a “clock” to regulate the biological activity of sensorin. Future understanding of the nature of these modifications will uncover new molecular mechanisms that contribute to target specificity and synapse formation. Synapse Formation and mRNA Localization in Cultured Aplysia NeuronsLyles et al.NeuronFebruary 02, 2006In BriefmRNA localization and regulated translation provide a means of spatially restricting gene expression within neurons during axon guidance and long-term synaptic plasticity. Here we show that synapse formation specifically alters the localization of the mRNA encoding sensorin, a peptide neurotransmitter with neurotrophin-like properties. In isolated Aplysia sensory neurons, which do not form chemical synapses, sensorin mRNA is diffusively distributed throughout distal neurites. Upon contact with a target motor neuron, sensorin mRNA rapidly concentrates at synapses. Full-Text PDF Open Archive" @default.
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• W2072130720 title "Think Globally, Act Locally: Local Translation and Synapse Formation in Cultured Aplysia Neurons" @default.
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• W2072130720 doi "https://doi.org/10.1016/j.neuron.2006.01.011" @default.
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