Current Research and Scholarly Interests
Human thought and perception, emotions and actions universally depend on signaling between neurons in the brain. This signalling largely happens at synapses, specialized intercellular junctions formed by pre- and postsynaptic neurons. When stimulated, a presynaptic neuron releases chemical messagescalled neurotransmitters that is recognized by a postsynaptic neuron.
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 neuropsychiatric illnesses, such as autism or neurodegenerative disorders.
Born in Germany, Südhof obtained a medical degree from the University of Gottingen in 1982. He became familiar with neuroscience when he performed research for his doctoral degree at the Max Planck Institute for Biophysical Chemistry. His thesis dealt with the release of hormones from adrenal cells, a model of neurotransmitter release.
To expand his knowledge of biochemistry and molecular biology, Südhof 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. He 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.
In 1986, Südhof started his own laboratory at UT Southwestern. He began his inquiry into the presynaptic neuron. At the time, what scientists mainly knew about the presynaptic neuron was 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 release? How did release occur at the specific region of the neuronthe 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 discoveries in his 20 years of research, Südhof revealed how synaptotagmin proteins sense calcium and mediate neurotransmitter release from presynaptic neurons. He also defined the molecules that organize release in space and time at a synapse, such as RIMs and Munc13's, and identified central components of the presynaptic machinery that mediate the fusion of synaptic vesicles containing neurotransmitters with the presynaptic plasma membrane, the process that ultimately causes 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 bind to each other at the synapse. There are many types of neurexins and neuroligins. Their variable pairing shapes the wide variability in the types of synapses in the brain. Mutations in these proteins severely impair synapse function in mice, and contribute to the pathogenesis of disease such as autism and schizophrenia in humans.
At present, Südhof's lab attempts to build on these findings in defining the relationship between specific synaptic proteins and information processing in the brain, with its concordant manifestations in behavior. This large-scale project attempts to provide insight both into the mechanisms undelying synaptic communication, and the processes causing human disease.
