Thomas Biederer, PhD

Bridging the cleft to induce synapse formation

How do synapses form? Select trans-synaptic interactions are now known to guide synapse development and we have identified and characterized synaptogenic cell adhesion molecules. One of these molecules, the immunoglobulin protein SynCAM 1, is required and sufficient to drive excitatory synapse formation in vivo. We build on this progress and analyze the functions of different synaptogenic adhesion proteins and how they cooperate.

In addition, we map the macromolecular and topological organization of the cleft of synapses using superresolution imaging and EM approaches. Our data support the concept that the synaptic cleft is comprised of structurally and molecularly diverse nanodomains. We are now testing the idea that the cleft is not static as widely assumed but a dynamic compartment, using methodologies including single particle tracking in live neurons. These studies can reveal how the sub-synaptic organization and dynamics of the cleft contribute to synaptic functions.

Synaptogenic signaling pathways

The intracellular signaling mechanisms instructing synapse development remain incompletely understood. Our work has shown that SynCAMs have signaling roles and we are elucidating these pathways. Analyzing synaptic changes in vivo, we have applied proteomic studies of synapses in mouse models with altered synaptogenesis to dissect signaling pathways. One example is our identification of the GTPase activator Farp1 as a novel postsynaptic protein that acts downstream of SynCAM adhesion and Semaphorin/Plexin signaling to promote synapse number and dendrite differentiation. We continue to elucidate how signaling pathways are integrated to control dendrite and synapse development.

Tuning networks

Synapse-organizing proteins not only allow neurons to connect but also impact neuronal networks once they are formed. This is underlined by a wealth of studies including from our group that synaptic adhesion proteins can modulate synaptic plasticity and impact memory processes. We address how synapse-organizing proteins contribute to the remodeling of neuronal connections. On the one hand, we investigate hippocampus-dependent memory processes. On the other, we use the paradigm of visual system plasticity to determine roles of trans-synaptic interactions in the experience-dependent maturation of cortical networks. This approach is based on in vivo electrophysiological recordings. Our work has translational potential as synaptic aberrations are a hallmark of autism-spectrum disorders and schizophrenia.