Molecular and
Cellular Physiology

Thomas Südhof

2013 Nobel Prize Winner

For a person to think, act, or feel, the neurons in her or his brain must communicate. This communication occurs at synapses, specialized junctions that allow neurons to exchange information on a millisecond timescale. When stimulated, a presynaptic neuron releases a chemical neurotransmitter signal that diffuses across the synaptic cleft to react with postsynaptic receptors. cells. Thomas Südhof’s laboratory studies how synapses form in the brain, how their properties are specified, and how they accomplish the rapid and precise signaling that forms the basis for all information processing by the brain. Moreover, as increasing evidence links impairments in synaptic transmission to diseases such as Alzheimer’s and autism, Südhof’s interests have include understanding possible molecular mechanisms contributing to these and related disorders.

The projects in the Südhof laboratory are guided by two overall directions that are closely related to each other, and linked to different psychiatric diseases.

First, the Südhof laboratory is interested in understanding how synapses are formed. Synapses exhibit a high degree of specificity in terms of which neurons they connect, and an astounding diversity in terms of physiological properties. Here, Südhof’s laboratory is focusing on synaptic cell-adhesion molecules, in particular neurexins and neuroligins that are essential components of synapses. The laboratory would like to understand how these molecules, and their many intra- and extracellular binding partners, shape the properties of synapses, such that their function is among the key determinants for the formation and specification of synapses. Moreover, neurexins and neuroligins mutations have been observed in autism spectrum disorders and in schizophrenia, suggesting that their role in shaping synaptic communication is impaired in these diseases. To study how neurexins and neuroligins shape synapse properties and how their dysfunction contributes to disease, the Südhof laboratory uses an interdisciplinary approach ranging from mouse genetics to behavior and electrophysiology.

Second, the Südhof laboratory would like to understand how information transfer is triggered at a synapse rapidly and precisely. Work in the laboratory over the last two decades demonstrated that the neurotransmitter signal is released when calcium in the presynaptic neuron binds to a protein called synaptotagmin, which serves as the switch for release. Release then occurs by fusion of neurotransmitter-containing vesicles at the active zone of the presynaptic neuron. The Südhof laboratory now focuses on understanding how this fusion process works, how calcium regulates fusion beyond binding to synaptotagmin, and how fusion becomes impaired in neurodegenerative diseases that appear to involve, at least in part, dysfunction of some of the fusion proteins. Understanding these issues will allow a complete view of how a synapse release neurotransmitters, and provide insight into neurodegenerative diseases.

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