Joint press release from Charité and Max Delbrück Center
The moment in which a nerve cell releases its neurotransmitters into the synaptic cleft is extremely short. Researchers at the Charité – University Medicine Berlin and the Max Delbrück Center managed to capture it microscopically. They now show the images of the merging vesicles in the journal Nature Communications*.
The process only takes a few milliseconds: A vesicle filled with neurotransmitters and only a few nanometers in size approaches the cell membrane, fuses with it and releases its messenger substances into the synaptic cleft – so that they can attach to the next nerve cell there. A team around Prof. Christian Rosenmund, last author of the publication and deputy director of the Institute for Neurophysiology at the Charité, captured this crucial moment for the work of the brain in microscopic images.
Point-shaped connections
“Until now, no one knew how the synaptic vesicles fuse with the cell membrane in detail,” says the first author of the study, Dr. Jana Kroll, who is now in the “Structural Biology of Membrane-Associated Processes” working group Prof. Oliver Daumke conducts research at the Max Delbrück Center. “In our experiments with mouse neurons, we were able to show that a point-shaped connection initially forms. This tiny stalk then expands into a pore through which the neurotransmitters enter the synaptic cleft,” explains Jana Kroll.
“With the help of the technology developed over five years, it has been possible for the first time to watch synapses at work without disturbing them,” adds Christian Rosenmund. “Jana Kroll has done real pioneering work here,” says the scientist, who is also on the board of the NeuroCure excellence cluster.
Flash frozen in ethane
In order to observe the synapses in real time, the researchers used nerve cells from mice that they had previously modified using optogenetics so that the cells were activated by a light signal – and then immediately began to release neurotransmitters. Within one to two milliseconds, the team then shock-frozen the neurons in ethane at minus 180 degrees Celsius. “With this process, plunge freezing, all cellular processes immediately stop and can be made visible using an electron microscope,” explains Jana Kroll.
The scientists came across another interesting detail: “We were able to see that most of the merging vesicles are connected to at least one other vesicle via small filaments – as soon as one vesicle fuses with the cell membrane, the next one is ready,” reports Jana Kroll. “We assume that this direct form of vesicle recruitment enables neurons to send signals over a longer period of time and thus maintain their communication.”
Treat epilepsy better
The fusion of vesicles that the team visualized occurs millions of times in our brains every minute. Understanding the process in detail is also important for medical purposes: “Mutations in proteins that are involved in vesicle fusion are known to be present in many people with epilepsy or other synapse diseases,” explains Christian Rosenmund. “If we uncover the precise role of these proteins, we can more easily develop targeted therapies for such synaptopathies.”
“The approach presented to us for time-resolved cryo-electron microscopy using light is not limited to neurons, but can be used in many areas of structural and cell biology,” adds Jana Kroll. She would now like to repeat her experiments at the Max Delbrück Center initially with human neurons that she obtains from stem cells. However, the researcher announces that this will not be an easy task: “The cells need around five weeks in the laboratory until they develop the first synapses and are extremely sensitive.”
*Kroll J et al. Dynamic nanoscale architecture of synaptic vesicle 2 fusion in mouse hippocampal neurons. Nat Comm 2025 13. doi: 10.1038/s41467-025-67291-6
About the study
The images were taken in the CFcryo-EM (Core Facility for cryo-Electron Microscopy), the joint technology platform of Charité, Max Delbrück Center and FMP (Leibniz Research Institute for Molecular Pharmacology), which is led by Dr. Christoph Diebolder is directed. Also significantly involved in the study Prof. Misha Kudryashev, head of the “In Situ Structural Biology” working group at the Max Delbrück Center, and Dr. Magdalena Schacherl, who heads the “Structural Enzymology” working group at the Charité.
The images may only be used free of charge in the editorial context of current reporting on the content of the press release. Use is only permitted if the author is named.
Links
Original publication
AG Rosenmund
AG Daumke
CFcryo-EM
Contact
Prof. Christian Rosenmund
Institute of Neurophysiology
Charity – University Medicine Berlin
T: +49 30 450 539 145
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