Professor Thomas C. Südhof won the Nobel Prize in Physiology or Medicine in 2013, jointly with Profs. James E. Rothman and Randy W. Schekman “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells”.

Chemical Messages: How Neurons Communicate

Right now, as you read these words, billions of cells called neurons in your brain are busy talking to each other. Much like you might speak to a friend standing nearby, neurons communicate across a tiny space between them called a synapse (Figure 1A). They send their messages using chemicals known as neurotransmitters (Figure 1B). The brilliant experiments of Bernard Katz in the 1950s and 1960s [1, 2] confirmed that neurons communicate via chemical messengers.

But this raised an intriguing question that was debated for many years by famous neuroscientists (scientists who study the brain and nervous system): why does the brain rely on chemicals traveling across a gap instead of simply passing electricity directly from one neuron to the next? Direct electrical connections called gap junctions exist in all animals and dominate in simple animals like worms. They even connect some cells in your brain. So why not use these connections for all neuron communication? The debate was finally resolved by Katz, and, for his important contributions to the topic of neuron communication, he won the Nobel Prize in Physiology or Medicine in 1970. But why would the brain “choose” chemicals over electricity for communication?

The answer is: flexibility and “brain power”. A gap junction has only two states, like a simple on-off switch—either electricity passes or it does not. A chemical synapse has many more possible states because chemical signals come in tiny packages called synaptic vesicles. When many vesicles are released by the sending neuron over a short time, the signal is stronger. When fewer vesicles are released, it is weaker. The receiving neuron responds differently depending on how much signal it receives (Figure 1C). This means every synapse can adjust its signal strength based on how it is being used, the timing of signals, and influences coming from outside the synapse (e.g., signals from other neurons, body chemicals, or environmental effects). This makes each synapse like a “nano-computer” that processes information rather than simply passing it along (Figure 1D). This adjustable signaling gives the brain far greater power, or computation ability, than if synapses just transferred unchanging electrical signals.

Fusion: The Cellular Zipper Mechanism

The work of great scientists like Bernard Katz revealed that the release of neurotransmitters from vesicles occurs through a process called vesicle fusion, where the vesicle inside the sending neuron merges, or fuses, with the sending neuron’s cell membrane, thereby releasing the neurotransmitters into the synapse (to learn more about vesicle fusion, read this article). It was also known that fusion and neurotransmitter release depend on calcium. Many people know calcium as a mineral that helps build strong bones and teeth, but inside cells, calcium also acts as an important signal. In neurons, a sudden rush of calcium tells vesicles that it is time to release their neurotransmitters. Remarkably, this entire process happens at an incredible speed of less than 1 ms!

When I started studying neurotransmitter release, how this unbelievably fast process happens at the molecular level was unknown. Many brilliant scientists who studied fusion, including Reinhard Jahn, James Rothman, and Randy Schekman, discovered proteins called SNAREs that sit on the vesicle membrane and are essential for vesicle fusion. Through collaborative work, we discovered that SNARE proteins bind to another group of proteins called SM proteins, which sit on the neuron’s cell membrane [3]. In the resting state, the vesicle is held very close to the membrane by the binding forces of these two protein groups. You can think of the SNARE complex as a zipper that closes from the end farthest from the membrane toward the membrane itself. In the resting state, this zipper is only half closed—keeping the vesicle tightly attached but not yet fused. So, what makes the zipper close completely and release the neurotransmitters?

Calcium Triggering: Rapid, Precise, and Cooperative

We decided to address this question by figuring out what synaptic vesicles are made of. My collaborators and I did that by systematically identifying every protein found in those vesicles. Some scientists doubted that this approach would succeed, but scientific discoveries often require testing ideas that others consider risky. We decided to pursue it and see what we could learn. We isolated protein after protein, studying what each one does. Some turned out not to do much—disappointing, but that is a natural part of science.

One of the proteins we found in synaptic vesicles was synaptotagmin. When we figured out its structure, we got very excited because it had two arm-like regions called C2 domains. C2 domains had been seen before in another protein that was known to respond to calcium. That made us think that synaptotagmin might bind (stick to) calcium in the process of synaptic vesicle fusion.

We continued to study synaptotagmin and showed, for the first time, that it binds to membrane molecules called phospholipids when calcium is present. This led to our big hypothesis: synaptotagmin might be a type of sensor that responds to calcium to trigger neurotransmitter release [4, 5]. The logic was clear—fusion involves membranes joining together, neurotransmitter release is dependent on calcium, and synaptotagmin binds membranes specifically when calcium is present. It took about 15 years and many more experiments to prove that this hypothesis was correct—synaptotagmin is indeed the calcium sensor that kickstarts neurotransmitter release.

But synaptotagmin does not work alone—it collaborates with another protein called complexin (Figure 2) [6]. Complexin binds to the SNARE proteins, keeping them ready and waiting for fusion. When calcium binds to synaptotagmin, synaptotagmin and complexin work together to finish “zipping up” the SNAREs, allowing the synaptic vesicle and cell membrane to fuse and release the neurotransmitter across the synapse (To see how the fusion occurs, watch this video). We know that complexin is an essential partner, though we still do not completely understand the details of how it works at the molecular level. This is one of the interesting puzzles left for future scientists!

Synaptotagmin Siblings

Over the years, we discovered that there are 16 different synaptotagmins, called synaptotagmin-1 to synaptotagmin-16. Eight of them bind calcium, and four of them work specifically in brain neurotransmitter release: synaptotagmins 1, 2, 7, and 9. Interestingly, some of their functions are similar while other ones differ.

Synaptotagmin-1 and synaptotagmin-2 are almost interchangeable, except synaptotagmin-2 is much faster (Figure 3). That is why synaptotagmin-2 is found at the contact point between nerve cells and muscles, where it helps muscles to contract very fast! Synaptotagmin-7 is the slowest of the four, kicking in when there is a relatively long, repeated release of neurotransmitters across synapses—like during continuous movements such as walking or playing an instrument. Synaptotagmin-9 is in the middle in terms of speed. Because each synaptotagmin works at its own speed, they are found in in different regions of the brain depending on what each synapse needs. Interestingly, these four synaptotagmins also take part in the fusion of vesicles in other types of cells outside the brain that are dependent on calcium triggering. One example is cells that release hormones like insulin and adrenaline.

Can Fusion Go Wrong?

The fusion machinery of neurons is so fundamental that when it malfunctions, the consequences can be severe. Scientists have identified families with mutations in synaptotagmins that cause serious brain diseases in childhood. There are also disorders in which the body’s defense system mistakenly attacks synaptotagmin, interfering with the signals from nerves to muscles and causing muscle weakness.

Other diseases affect different fusion proteins. Botulism and tetanus, for example, are caused by bacterial toxins that attack SNARE proteins, blocking communication between neurons and leading to an inability to move, called paralysis. Fortunately, such cases are rare—the fusion machinery is so essential that if it goes wrong, there is a good chance that the person will not survive for long.

Our Brains vs. Computers

Remember that each synapse can work like a tiny “nano-computer”, adjusting the strength of its signals in many ways? This flexibility is one reason brains are so powerful. While computers usually work with simple on-off signals, synapses can constantly fine-tune their communication. Each time they are used, synapses can become stronger, weaker, or change in other ways. This ability to change is called plasticity, and it is one of the foundations of learning and memory.

The molecular machinery you learned about in this article is what makes this flexibility possible. Proteins such as synaptotagmin, SNAREs, and complexin ensure that neurotransmitters are released with incredible speed and precision, while allowing each synapse to adjust how strongly it communicates. Because billions of synapses can each fine-tune their signals independently, the brain is not simply a collection of wires—it is a vast network of tiny information-processing units that are constantly changing as we learn and experience the world.

This is why your brain can do many things that today’s artificial intelligence systems still struggle with: learning from only a few experiences, adapting to unexpected situations, and combining memories, emotions, and knowledge to understand the world. But the brain’s strength also comes with a weakness: our memories are not perfect recordings, like files saved on a computer. They are flexible and changeable—which sometimes makes them inaccurate, but also allows us to keep learning and growing throughout life.

As a young scientist, you are entering neuroscience at an exciting time. One of the great challenges for future scientists is to understand how the brain works—from the tiny changes that happen at individual synapses to the way billions of synapses work together in vast networks. Solving this mystery could teach us much more about who we are as humans. Maybe you will help uncover the next great secret of the brain!

Glossary

Synapse: ↑ A tiny physical gap between neurons where chemical communication occurs.

Neuro Transmitters: ↑ Chemical messengers that carry signals from one neuron to another across the synapse.

Gap Junction: ↑ A tiny channel that directly passes electrical signals between neurons.

Synaptic Vesicles: ↑ Small membrane-bound bubbles inside neurons that store and release neurotransmitters.

Fusion: ↑ The process in which a vesicle merges with the neuron’s outer membrane to release neurotransmitters.

SNAREs: ↑ A group of proteins that pull the vesicle and cell membranes together like a zipper to enable fusion.

SM Proteins: ↑ Helper proteins that collaborate with SNAREs to make sure vesicle fusion works smoothly.

Plasticity: ↑ The ability of synapses and brain circuits to change their strength and function based on experience.

Acknowledgments

We wish to thank Iris Gat for providing the figures and Susan Debad for copyediting the manuscript.

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