Researchers develop first 3-D model of synapse
GÖTTINGEN & BERLIN, Germany: The molecular architecture of synapses has been unknown until now. A research team from Göttingen has managed to determine the copy numbers and positions of all of the important building blocks of a synapse for the first time. This has allowed them to reconstruct the first scientifically accurate 3-D model of a synapse. In the future, these findings are hoped to contribute to the identification of anomalies in neuronal anatomy in neurodegenerative diseases, such as Parkinson’s disease.
This effort was made possible by the collaboration of specialists in electron microscopy, super-resolution light microscopy, mass spectrometry, and quantitative biochemistry at the University Medical Center Göttingen (UMG), the Max Planck Institute for Biophysical Chemistry, also in Göttingen, and the Leibniz Institute for Molecular Pharmacology in Berlin. The project was funded by the European Research Council (ERC) and the Deutsche Forschungsgemeinschaft (DFG).
“This 3-D model of a synapse opens a new world to neuroscientists,” said Prof. Silvio Rizzoli, from the Center for Nanoscale Microscopy and Molecular Physiology of the Brain at the UMG, as well as senior author of the publication. Particularly the abundance and distribution of the building blocks have long been terra incognita. The model presented by Rizzoli and his team now shows hundreds of thousands of individual proteins in correct copy numbers and at their exact localisation within the nerve cell.
“The new model shows for the first time that widely different numbers of proteins are needed for the different processes occurring in the synapse,” said Dr Benjamin G. Wilhelm, first author of the publication. The new findings establish that proteins involved in the release of messenger substances (neurotransmitters) from synaptic vesicles are present in up to 26,000 copies per synapse. Proteins involved in the opposite process, the recycling of synaptic vesicles, however, are present in only 1,000–4,000 copies per synapse.
These details help to resolve a long-standing controversy in neuroscience: how many synaptic vesicles within the synapse can be used simultaneously? Apparently, more than enough proteins are present to ensure vesicle release, but the proteins for vesicle recycling are sufficient for only 7 to 11 per cent of all vesicles in the synapse. This means that the majority of vesicles in the synapse cannot be used simultaneously.
The most important insight offered by the new model is, however, that the copy numbers of proteins involved in the same process scale to an astonishingly high degree. The building blocks of the cell are tightly co-ordinated to fit together in number, comparable to highly efficient machinery. This is a surprising finding and it remains entirely unclear as to how the cell manages to co-ordinate the copy numbers of proteins involved in the same process so closely.
The new model will serve as a reference source for neuroscientists of all specialisations in the future, and will support future research, since the copy number of proteins can be an important indicator of their relevance. The research team led by Rizzoli does not, however, plan to stop there: “Our ultimate goal is to reconstruct an entire nerve cell”. Combined with functional studies on the interaction of individual proteins, this would allow the simulation of cellular function in the future—the creation of a virtual cell.
For his approach to studying the molecular anatomy of nerve cells, Rizzoli was awarded an ERC Consolidator Grant in 2013. “The findings of Prof. Rizzoli are spectacular,” said Prof. Heyo Kroemer, speaker of the UMG managing board and Dean of the Faculty of Medicine at the University of Göttingen. “This highly precise synaptic model will provide completely new possibilities for medical research. This is another example demonstrating that the University Medical Center Göttingen provides attractive conditions for international top-level research.”
The study, titled “Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins”, was published in the May issue of the Science journal.