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Research Shows Synapses are Always Ready to Go

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The inner workings of the brain are quick, but really they have to be. Neurons need to be able to rapidly propagate information in their interior via electrical signals and they communicate with each other at special contact points known as the synapses. These chemical messenger substances (known as neurotransmitters) are stored in vesicles at the synapses. When a synapse becomes active, some of these vesicles fuse with the cell membrane and release their contents. To ensure that valuable time is not lost, synapses always have some readily releasable vesicles on standby.

With the help of new high-resolution, three-dimensional electron microscopy techniques, scientists succeeded in demonstrating that these fusionable vesicles have a very special characteristic: they already have close contact with the cell membrane long before the actual fusion occurs.

But there is more, the research team also decoded the molecular machinery that facilitates the operation of this docking mechanism.

The fusion of the neurotransmitter vesicles with the cell membrane involves close cooperation between numerous protein components, which monitor each other and ensure that every single ‘participant’ is always in the right place. This is referred to as the fusion machinery and the comparison is an apt one: if a cogwheel in a clock for example is broken, the hands do not move. In a similar way, faulty or missing molecules impair synaptic operations.

In research studies carried out some years ago, the team already demonstrated that the transmission of information at the synapses in genetically modified mice, in which all known genes of the Munc13 or CAPS proteins had been switched off, is severely defective. Although the neurons of the genetically modified mice do not differ from those of healthy mice when examined under an optical microscope, if Munc13 is missing, the release of neurotransmitters actually grinds to a halt completely.

The findings showed that to be able to react immediately to signals at all times, each synapse must keep a small number of ‘readily releasable’ fusionable vesicles on standby.

But how do Munc13 and CAPS convert the vesicles to this kind of fusionable state? To answer this question, the scientists studied the synaptic contacts in the minutest possible detail. To do this, neurobiologists used a high-pressure freezing process. This involves the rapid freezing of neurons in the brain tissue under high pressure so that no disruptive ice crystals are formed and the fine structure of the cells is particularly well conserved, this task is easier said than done.

Three-dimensional reconstruction of a synapse in the mouse brain. Readily releasable fusionable synaptic vesicles (blue, around 45 millionths of a millimetre in diameter) are docked at the cell membrane.

Three-dimensional reconstruction of a synapse in the mouse brain. Readily releasable fusionable synaptic vesicles (blue, around 45 millionths of a millimetre in diameter) are docked at the cell membrane.
Image credit goes to Max Planck Institute of Experimental Medicine

Then the samples obtained using this method were analysed using electron tomography. The electron microscope images of a structure are recorded from many different angles, in a similar way to the process used in medical computed tomography. The individual images can then be combined on the computer to give a high-resolution three-dimensional image – in this case of the synapse.

“Our results showed that readily releasable vesicles in healthy synapses touch the cell membrane,” explains Dr. Benjamin H. Cooper, lead researcher.“However, if Munc13 and CAPS proteins are missing, the vesicles do not reach the active zone and accumulate a few nanometres away from it.”

To their astonishment, the researchers also observed that SNARE proteins, which collaborate with Munc13 and CAPS in the nerve endings, are also involved in this docking process. SNARE proteins are found in the cell and vesicle membranes of healthy synapses and control the fusion of the two membranes during neurotransmitter release. When a vesicle approaches the cell membrane, the individual SNARE molecules line up opposite each other like the sides of a zip and pull the membranes close to each other in this way. The vesicles await the starting signal for their fusion in this state, they are always ready for this signal.

The findings of the neurobiologists prove that Munc13, CAPS and SNARE proteins closely align the vesicle and cell membrane in the synapse, long before the signal for fusion is given. This is the only way that the fast and controlled transmission of information at the synapse can be guaranteed, thanks to which we can react specifically to information from our environment.

“It had long been clear that synapses have to be extremely fast to carry out all of the many complex brain functions. Our study shows for the first time how this is managed at the molecular level and on the level of the synaptic vesicles,” says Nils Brose.

Because almost all of the protein components involved in this process also play a role in neurological and psychiatric diseases, the team believe that their discovery will soon benefit medical research. An exciting prospect no doubt, after all there are a lot of implications for a finding such as this.

Sources

Imig, C., Min, S., Krinner, S., Arancillo, M., Rosenmund, C., Südhof, T., Rhee, J., Brose, N., & Cooper, B. (2014). The Morphological and Molecular Nature of Synaptic Vesicle Priming at Presynaptic Active Zones Neuron, 84 (2), 416-431 DOI: 10.1016/j.neuron.2014.10.009

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