For people to have ideas, to experience happiness, or to remember the lyrics of a song, the neurons in their brains must communicate. This communication occurs in a manner similar to a relay racer passing a baton from one runner to the next.
When stimulated, a presynaptic neuron releases a "baton" in the form of a chemical messenger—called a neurotransmitter—across a synapse, a small gap between the cells in the brain. Then, a postsynaptic neuron absorbs the message and conveys it to subsequent neurons.
For decades, the majority of neuroscientists focused their research on postsynaptic neurons and their role in learning and memory. But throughout his career, Thomas Südhof has studied the presynaptic neuron. His collective findings have contributed to much of our current understanding of how a presynaptic neuron releases neurotransmitters and, more recently, how synapses form. His work also has revealed the role of presynaptic neurons in psychiatric illnesses, such as autism.
Born in Germany, Südhof obtained a medical degree from the University of Göttingen in 1982. He got a taste for neuroscience when he performed research for his doctoral degree at the Max-Planck-Institute for Biophysical Sciences under Victor P. Whittaker, a pioneer in neurochemistry. To expand his knowledge of biochemistry and molecular biology, Südhof then started to work in 1983 as a postdoctoral fellow at the laboratories of Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center at Dallas.
There, Südhof cloned the gene for the receptor of LDL (the low-density lipoprotein), a particle in the blood that transports cholesterol. Moreover, his work identified the sequence that mediates the regulation of the LDL receptor gene expression by cholesterol. While Südhof was in their laboratories, Brown and Goldstein won the Nobel Prize in Physiology or Medicine in 1985 for their discoveries related to the regulation of cholesterol metabolism.
Soon after, in 1986, UT Southwestern offered Südhof the opportunity to start his own laboratory. He began his inquiry into the presynaptic neuron. At the time, what scientists mainly knew about the presynaptic neuron is that calcium ions stimulate the release of neurotransmitters from membrane-bound sacs called vesicles into the synapse, in a process that takes less than a millisecond. This release involved fusion of the vesicles with the plasma membrane, but how such fusion occurs, and how it is triggered by calcium was unknown.
Südhof decided to try to answer these questions.
Südhof’s work revealed that fusion of the synaptic vesicles, the small sacs filled with neurotransmitters, involves an obligatory catalytic protein called Munc18-1 that acts in conjunction with an protein machine made up of so-called SNARE proteins that were described by others and provide the muscle to the brawn of Munc18-1. Strikingly, the function of Munc18-like and SNARE-type proteins generally applies to most fusion reactions in biology, not only to synapses.
More importantly, Südhof’s work how calcium controls fusion at the synapse: He showed that calcium binds to synaptotagmin proteins, thereby stimulating synaptotagmins to trigger rapid neurotransmitter release. Again, Südhof’s work revealed that synaptotagmins also act as universal calcium sensors in non-neuronal cells, for example for release of hormones in non-neuronal cells.
Furthermore, his work described how a complex of organizing proteins, containing RIM and Munc13 proteins as central coomponents, embed the fusion machinery into the presynaptic nerve terminal. The RIM/Munc13 complex recruits and prepares vesicles for fusion, and tethers calcium channels in the plasma membrane next to the release sites to allow rapid coupling of neuronal excitation to neurotransmitter release.
In more recent studies that intensified after Südhof moved to Stanford in 2008, Südhof's work examined how pre- and postsynaptic proteins form physical connections during synapse formation. Specifically, he identified proteins on presynaptic neurons called neurexins, and proteins on the postsynaptic neuron called neuroligins and LRRTMs, that come together and bind to each other across the synaptic cleft. There are many types of neurexins and neuroligins, and the pairing of any two helps create the properties of a synapse and the wide variability in the types of connections in the brain, Südhof says.
The coming together of neurexin and neuroligin at the synapse is very important for normal brain function. Alterations in these proteins impairs the brain's chemistry, as uncovered in recent human genetics studies showing that mutations in neurexin or neuroligin genes can cause schizophrenia or autism. Südhof has shown that these mutations, when introduced into mice, change the properties of synapses and impair neurotransmission. His current studies aim to clarify how neurexins, neuroligins, and other proteins control synapse formation and synapse function, and how they mediate synapse remodeling during learning or other adaptive changes of the brain. Progress in such studies will help our understanding on how the brain is wired normally, and how such wiring becomes impaired in neuropsychiatric diseases.