About Our Work

Neurexins are essential presynaptic cell adhesion molecules that are linked to schizophrenia and autism and are subject to extensive alternative splicing.
Aoto et al, Cell 2013

For a person to think, act, or feel, the neurons in a person’s brain must communicate continuously, rapidly, and repeatedly. This communication occurs at synapses, specialized junctions that allow neurons to exchange information on a millisecond timescale and that organize neurons in vast overlapping circuits. When stimulated, a presynaptic neuron releases a chemical neurotransmitter signal that diffuses across the synaptic cleft to react with postsynaptic receptor neurons or muscle 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. The formation and specification of synapses, their properties and plasticity determine the input-output relations of neural circuits, and thus underlie all brain function. Moreover, increasing evidence links impairments in synaptic transmission to disorders such as Alzheimer’s diseases, schizophrenia, and autism, and Südhof’s laboratory aims to contribute to the understanding of these and related disorders.

Synapse formation

First, the Südhof laboratory is interested in understanding how synapses are formed and specified. The goal of this work is to understand the molecular determinants that shape the function of synapses as the fundamental information processing units in neural circuits, with the overall aim of defining the molecular logic that operates in these circuits. 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 that are essential presynaptic components of synapses and that interact with multifarious postsynaptic cell-adhesion molecules to shape synapse properties.

The laboratory would like to understand how neurexins and their many intra- and extracellular binding partners shape the properties of synapses. Moreover, mutations in neurexins and their ligands, chiefly neuroligins, 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 structural biology and mouse genetics to electrophysiology and mouse behavior.

In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic and behavioral changes.
Rothwell et al, Cell 2014

Synapse communication

Second, the Südhof laboratory would like to understand the molecular basis for synaptic information transfer, and for the plasticity of this transfer. 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 neurotransmitter release is organized presynaptically and how its plasticity – that can result in up to 10-fold increases or decreases in release! – is effected. Moreover, the Südhof laboratory intensely studies how postsynaptic receptors are recruited to synapses, and how the plasticity of postsynaptic receptor function, both on short- and long-term timescales, is mediated in molecular terms by regulation of postsynaptic membrane traffic. Understanding these issues will allow a more complete view of how synapses function.