Neurons communicate by sending chemical signals called neurotransmitters across synapses, specialized connections between two individual cells. This communication requires a delicate and intricate molecular architecture. A recent paper published in Nature has now shown that the structure of this intercellular space is more complicated than previously thought, and it probably helps boost the efficiency of the signaling.

The authors of this paper imaged three proteins found in the cell that start the signaling process. (Generically called presynaptic proteins, the ones looked at here are RIM1, RIM2, Munc13, and bassoon.) Each of these proteins was specifically tagged, and the authors plotted the density of their distribution across the active zones of the synapse.

The team then developed an algorithm that allowed it to identify small clusters of proteins based on their local density. These nanoclusters were more likely to be located near the center of each synapse than near the synaptic edges. This wasn’t true of all the proteins, but at least two were tightly restricted and a third less so (bassoon was almost uniform throughout the synapse).

The researchers also tracked the distribution of proteins during synaptic transmission, when cells were using the synapses to send information. To do this, they used a fluorescent tagging technique that allowed them to see the formation of signaling components called vesicles.

The team found that if a region of the synapse had a high concentration of protein nanoclusters, then the region was more likely to generate a container filled with neurotransmitters that would eventually cross the synapse to the neighboring cell. In particular, one of the proteins they looked at (RIM1) was located in regions that would generate containers filled with neurotransmitters.

Some of these same RIM proteins are also found in the cell on the receiving side of the synapse, so the authors looked at the localization of the proteins there as well. Once again, the proteins formed tiny clusters. But the locations of those clusters were highly correlated with the ones on the cell that sends the signal. In other words, the neurons on both sides of the synapse had lined up their signaling components. This is striking, because, as far as we know, there’s nothing physical connecting the cells in this area.

As they looked into this relationship further, the researchers found that the protein alignment extended deeper into the receiving cell, influencing the location of proteins within its cell body and not just near the surface.

In one final experiment, the authors wanted to see if the nanoscale alignment of these proteins would be altered when the overall structure of the synapse was changing in response to cell needs. As they expected, they found that when they induced changes in the synapse, the nanostructure of the receiving cell was seriously disrupted, and the alignment between the nanoclusters on both cells was disturbed. Both sending and receiving cells underwent considerable reorganization during this experiment and only experienced partial recovery to protein alignment during the short observation period afterward.

The authors think that these experiments support the idea that protein density in neurons exists in what they call a nano-column, in which active areas of the signaling neuron are aligned to the most densely populated regions of the receiving cell. This precise and careful alignment of proteins on neural synapses may be a part of the optimization that neurons use to ensure that communication is extremely fast and effective. Future research on the localization and density of protein nanoclusters in neurons may provide further insight as to how this optimized communication comes about.

Nature, 2016. DOI: 10.1038/nature19058 (About DOIs).