Research & Publications
Understanding synapse development – and how we get there
How synapses form to wire neurons into networks is a fundamental question of neuroscience. We pursue four long-term goals to understand this process. First, we define on molecular and cellular levels the signals that induce synapse formation. Second, we elucidate the intracellular pathways that control synaptogenesis. Third, we determine how the experience-dependent remodeling of neuronal connections is modulated by synapse-organizing proteins. Fourth, we analyze how synaptic aberrations contribute to brain disorders and how the maturation of neuronal connectivity can be supported. To pursue our goals, we combine biochemical, cell biological, physiological, and in vivo approaches. This integration enables mechanistic insights into synapse development and the profound disease relevance of synaptic biology.
Extensive Research Description
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.
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.
Biochemistry; Central Nervous System; Neurology; Neurosciences; Synapses