About Our Work

Trans-synaptic network 

Interactions of candidate trans-synaptic adhesion molecules. The indicated molecules form vast molecular interaction networks that are thought to control the establishment and specification of synapses as well as various forms of synaptic plasticity. Modified from Südhof, Neuron 2018

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 into vast overlapping circuits.

Our 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 establishment 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. Thus, our laboratory also aims to contribute to the understanding of neuropsychiatric and neurodegenerative disorders.

Synapse formation
The goal of our work on synapse formation 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 constructs these circuits. Synapses exhibit a high degree of specificity. Neurons form synapses with only a select subset of other neurons, and the resulting synaptic connections exhibit an astounding diversity of properties that are specified by the pre- and postsynaptic neurons. Our laboratory is focusing on synaptic cell-adhesion molecules that form a dynamic network across the synaptic cleft to control for establishment and specification of synaptic connections between neurons. In addition, we are analyzing secreted synaptogenic molecules produced by neurons and glia or circulating in the blood that promote synapse formation and synaptic transmission.

Lphn-teneurin & -FLRT interactions

Different isoforms of latrophilins (Lphn2 and Lphn3) are specifically targeted to distinct dendritic domains of pyramidal neurons in the CA1 region of the hippocampus, where the latrophilins are instrumental in establishing synapses formed by specific presynaptic axons emanating from the CA3 region or the entorhinal cortex. Modified from Sando et al., Science 2019.

In these projects, our laboratory is studying a range of key synaptic adhesion molecules, such as neurexins and latrophilins that, together with their many intra- and extracellular binding partners, make and shape synapses. These molecules dictate the establishment of synapses, render synapses functional, and endow synapses with specific properties, such as the ability to undergo long-term potentiation. Moreover, mutations in neurexins and their ligands, chiefly neuroligins, are observed in autism spectrum disorders and in schizophrenia, suggesting that their role in shaping synaptic communication is impaired in these diseases. Furthermore, we are investigating how secreted glial proteins such as ApoE or SPARCL1 promote synapse formation by binding to specific cell-surface receptors. To study synapse formation and its impairments in disease, we use an interdisciplinary approach ranging from structural biology and mouse genetics to electrophysiology and behavior, using as model systems both mice and human neurons trans-differentiated from stem cell

Synapse modifications in memory
Long-term memories are thought to be mediated by changes in synapse numbers and synapse properties in defined neural circuits. How these changes are effected, however, remains unclear. Our laboratory is using our expertise in the molecular definition of synapses and in monitoring synaptic connections for a better understanding of how synapse modifications mediate learning and memory. Our focus here is not on specific circuits, but on defining the molecular changes that are generally required for learning long-term memories and how they relate to synapses, using again a broad range of techniques that include single-cell RNAseq, imaging, behavior, and protein chemistry.

SPARCL1 increases synapse numbers & potentiates synaptic responses

Imaging of excitatory vGluT1-positive and inhibitory vGAT-positive synapses (A) and electrophysiological recordings (B) show that SPARCL1 increases both synapse numbers and synaptic transmission, with a disproportionately higher increase in NMDA-receptor-mediated synaptic responses. These data illustrate a common reductionist approach in our lab to analyze mechanisms of synapse assembly. Modified from Gan and Südhof, J. Neurosci. (2020).

The Pathobiology of Synpses in neurodegenerative disorders
In a second line of research, our laboratory addresses the question of how neurodegenerative disorders cause a loss of synapses. This work focuses on ApoE and on APP, two proteins that are genetically linked to Alzheimer’s disease and other neurodegenerative disorders. ApoE is involved in lipid transport, but the relation of lipid transport to synapse formation and Alzheimer’s disease remains unclear and is a focus of our work. Despite decades of work, APP’s physiological and pathological roles remain incompletely understood, but APP has also been implicated in synaptic functions. Elucidating how ApoE and APP function at the synapse physiologically and how ther role at the synapse relates to neurodegenerative disorders thus is another general focus of our work.

 

 

Weekly Subgroup Zoom Meetings

Synaptogenic Factors Subgroup

Memory Subgroup

Neurexins Subgroup

ApoE Subgroup