Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments
Local translation in presynaptic terminals
Proteins carry out most of the functions in cells, including neurons, which are one of the most morphologically complex cell types in the body. This poses challenges for how proteins can be supplied to remote regions where connections (synapses) are made with other neurons. One solution to the neuron protein-supply problem involves the local synthesis of proteins from messenger RNA (mRNA) molecules located at or near synapses. Hafner et al. used RNA sequencing methods and superresolution microscopy to show that axon terminals contain hundreds of mRNA molecules as well as the machinery needed for protein synthesis. Furthermore, the axon terminals were able to use these components to make proteins that participate in synaptic transmission.
Science, this issue p. eaau3644
Structured Abstract
INTRODUCTION
The regulation of synaptic proteins by posttranslational modifications and by ongoing protein synthesis and degradation drives homeostasis and plasticity at synapses. A key question is where synaptic proteins are made. Most of the neuron’s volume comprises axons and dendrites that can be micrometers or millimeters long. Thus, a substantial fraction of proteomic remodeling could potentially occur locally within both axons and dendrites. Whereas there is wealth of data indicating that protein synthesis occurs in mature dendrites, there has been much less evidence in support of local translation in mature axons.
RATIONALE
Efforts to localize molecules or cell biological events to neuronal pre- or postsynaptic compartments by using fluorescence microscopy are limited by the tight association of the axonal bouton and the dendritic spine; the synaptic cleft, the only clear region of separation, is only ~20 nm wide. In this study, to increase the resolving power to visualize RNA molecules in pre- and postsynaptic compartments, we optimized fluorescence in situ hybridization (FISH) and nascent protein detection methods for use with expansion microscopy. To characterize transcripts and translational machinery in excitatory presynaptic terminals, we used a recently developed platform that couples fluorescence sorting with biochemical fractionation to sort and purify fluorescently labeled synaptosomes. To obtain direct evidence for protein synthesis in synaptic compartments, particularly presynaptic boutons, we adapted the puromycin-based metabolic labeling strategy for detection with electron or expansion microscopy. We also examined the translational signature of these three different forms of local protein synthesis–dependent plasticity in three different synaptic compartments: dendritic spines, excitatory terminals, and inhibitory terminals.
RESULTS
In adult rodent brain slices and cultured neurons, we found that >75% of both excitatory and inhibitory presynaptic terminals contain the machinery for protein synthesis: rRNA, ribosomes, and polyadenylated [poly (A)+] mRNA. Using mature mouse forebrain synaptosomes that are enriched for vGLUT1+ presynaptic terminals, we identified ~450 transcripts that were enriched (relative to the generic synaptosome transcriptome). These included many mRNAs that code for proteins that regulate neurotransmitter release. Both light microscopy (confocal and super-resolution) and electron microscopy revealed that in the absence of overt stimulation, there was a notably high level of ongoing protein synthesis in both pre- and postsynaptic compartments. After just 5 min of metabolic labeling, ~40% of both excitatory and inhibitory presynaptic terminals and ~60% of dendritic spines exhibited active translation. Three different forms of synaptic plasticity resulted in distinct patterns of protein synthesis stimulation in dendritic spines and in excitatory and inhibitory presynaptic axon terminals.
CONCLUSION
In this study, we investigated the localization and stimulation of protein synthesis in mature synapses. We unambiguously identified protein synthesis machinery and mRNA translation in individual synaptic compartments. Both excitatory and inhibitory presynaptic boutons (as well as postsynaptic spines) carry out protein synthesis regularly, in the absence of any exogenous stimulation. Synthesis within these three compartments is differentially recruited to modify local proteomes during synaptic plasticity. Local protein synthesis adds spatial and temporal precision for proteome remodeling that can be exploited to rapidly modify synapses in specific subcellular compartments.
Plasticity differentially recruits local protein synthesis.
Summary scheme indicating how protein synthesis occurs in both post- and presynaptic compartments and how each different form of plasticity examined has a specific translational signature. The three compartments represented, excitatory and inhibitory presynaptic boutons and postsynaptic spines, exhibit different patterns of enhanced protein synthesis (arrows) after the treatments with (S)-3,5-dihydroxyphenylglycine hydrate [metabotropic glutamate receptor long-term depression (mGluR LTD)], brain-derived neurotrophic factor (BDNF) (BDNF potentiation), or arachidonyl-2-chloroethylamide (endocannabinoid receptor activation).
Abstract
There is ample evidence for localization of messenger RNAs (mRNAs) and protein synthesis in neuronal dendrites; however, demonstrations of these processes in presynaptic terminals are limited. We used expansion microscopy to resolve pre- and postsynaptic compartments in rodent neurons. Most presynaptic terminals in the hippocampus and forebrain contained mRNA and ribosomes. We sorted fluorescently labeled mouse brain synaptosomes and then sequenced hundreds of mRNA species present within excitatory boutons. After brief metabolic labeling, >30% of all presynaptic terminals exhibited a signal, providing evidence for ongoing protein synthesis. We tested different classic plasticity paradigms and observed distinct patterns of rapid pre- and/or postsynaptic translation. Thus, presynaptic terminals are translationally competent, and local protein synthesis is differentially recruited to drive compartment-specific phenotypes that underlie different forms of plasticity.
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Supplementary Material
Summary
Figs. S1 to 13
Tables S1 and S2
Movie S1
Resources
Correction (13 February 2020): The NCBI accession number for the raw data has been added to the Acknowledgments.
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Science
Volume 364 | Issue 6441
17 May 2019
17 May 2019
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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 3 June 2018
Accepted: 2 April 2019
Published in print: 17 May 2019
Acknowledgments
We thank I. Bartnik, N. Fuerst, A. Staab, D. Vogel, and C. Thum for the preparation of cultured neurons; S. tom Dieck and T.W. Lee for important work in preliminary studies; H. Nguyen for experiments shown in Fig. 4H and fig. S7B; M. F. Angelo, A. Stum, and V. Pitard (flow cytometry facility, CNRS UMS 3427, INSERM US 005, University of Bordeaux, F-33000 Bordeaux, France) for technical assistance with FASS experiments; F. Cordelières (Bordeaux Imaging Center, University of Bordeaux, F-33000 Bordeaux, France) for image analysis routines; and G. Tushev for help with RNA sequencing analyses. Funding: A.-S.H. is supported by an EMBO long-term postdoctoral fellowship (ALTF 1095-2015) and the Alexander von Humboldt Foundation (FRA-1184902-HFST-P), as well as the National Infrastructure France–BioImaging, supported by the French National Research Agency (ANR-10-INBS-04). P.G.D.-A. is supported by the Peter and Traudl Engelhorn Foundation and the Alexander von Humboldt Foundation (USA-1198990-HFST-P). E.M.S. is funded by the Max Planck Society, an Advanced Investigator award from the European Research Council, DFG CRC 1080: Molecular and Cellular Mechanisms of Neural Homeostasis, and DFG CRC 902: Molecular Principles of RNA-based Regulation. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 743216). B.L. is funded by the Royal Society NZ–Germany Science and Technology Programme (FRG-UOO1403). E.H. is funded by the French National Research Agency (ANR-10-LABX-43 BRAIN Dolipran) and the Fondation pour la Recherche Médicale (ING20150532192). Author contributions: A.-S.H. and P.G.D.-A. designed, conducted, and analyzed experiments. E.H. and B.L. designed and supervised experiments. E.M.S. designed experiments, supervised the project, and wrote the paper. All authors edited the paper. Competing interests: The authors declare no competing financial interests. Data and materials availability: All data are available in the main text or the supplementary materials. The accession number for the raw sequencing data reported in this paper is NCBI BioProject: PRJNA544779.
Authors
Funding Information
European Molecular Biology Organization: ALTF 1095-2015
Alexander von Humboldt-Stiftung: FRA 1184902 HFST-P
H2020 European Research Council: 743216
Agence Nationale de la Recherche: ANR-10-LABX-43 BRAIN Dolipran
Fondation pour la Recherche Médicale: ING20150532192
France-BioImaging: Access-1576
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