For people to have ideas, experience happiness, or remember the lyrics of a song, the neurons in their brains must communicate. The exchange 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 chemical messages—called neurotransmitters—across a synapse, a small gap between the cells. Then, a postsynaptic neuron absorbs the message and conveys it to subsequent neurons.
For decades, the majority of neuroscientists focused their research on the postsynaptic neuron and its role in learning and memory. But throughout his career, Thomas Südhof has studied the presynaptic neuron. His collective findings have provided much of our current scientific understanding of presynaptic neuron behavior in neurotransmission and synapse formation. 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 Gottingen in 1982. He got a taste for neuroscience when he performed research for his doctoral degree at the Max Planck Institute for Biophysical Sciences. His thesis dealt with the release of chemicals from adrenal cells, a model of cellular discharge similar to that of a nerve cell.
To expand his knowledge of biochemistry and molecular biology, Südhof started to work in 1983 as a postdoctoral fellow at one of the best laboratories in the United States at the time: that of Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center at Dallas.
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 sequences that mediate the regulation of the LDL receptor gene expression by cholesterol. The receptor on liver cells binds LDL, thus removing cholesterol from circulation. While Südhof was in their laboratory, 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.
But much was unknown: What allowed rapid neurotransmitter discharge? How did release occur at the specific region of the neuron—the synapse? How did repeated activity change the presynaptic neuron? How did the pre- and postsynaptic neurons come together at the synapse?
Südhof decided to try to answer these questions.
Among the many discoveries in his 20 years of research, Südhof revealed how synaptotagmins, proteins that sense calcium ions and bind to other proteins, facilitate either quick or slow neurotransmitter release from the presynaptic neuron. He also found RIMs and Munc13s—proteins that help fuse neurotransmitter vesicles to the presynaptic nerve cell membrane and enable the nerve cell to transmit messages more easily with experience. Furthermore, his work identified central components of the presynaptic machinery mediating the fusion of the vesicles with the presynaptic plasma membrane, the process that effects neurotransmitter release and that is controlled by synaptotagmins.
Südhof's work also revealed how pre- and postsynaptic proteins form physical connections, permitting neurotransmission. Specifically, he identified proteins on presynaptic neurons, called neurexins, and proteins on the postsynaptic neuron, called neuroligins, that come together and bind at the synapse. 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 the proteins will affect the brain's chemistry. Südhof has shown that in cases of inherited autism, mutations in either of the genes that code for the neurexin and neuroligin proteins impair neurotransmission.
Although Südhof has made great strides in revealing the complexity of the presynaptic neuron and its role in nerve signal transmission and synapse formation, he continues to expand on his prior research. It remains unclear, for example, how neurexins and neuroligins find each other and how their production and variability are controlled.
Südhof recently has begun to collaborate with researchers at Janelia Farm, HHMI's research facility, to develop mouse models that would make it easier to study synapse genes. The project will take many years. Südhof hopes that the cooperative effort will help advance and integrate knowledge about both sides of the synapse, and in many other areas of neuroscience.
