Deconstructing the Molecular Assembly of Synaptic Connections

Synapses constitute the minimal computational units of our brains, and synaptic imbalances underlie (neuro)psychiatric diseases.

Synapses are formed continuously throughout life by processes thought to be orchestrated by specific cell adhesion interactions between contacting pre- and post-synaptic neurons, but their regulation and downstream signals are not well understood.Funded by a VR Starting Grant, I have established a fully independent lab to address these questions.

We have developed a human genetic model system of neurons in which formation of synapses are uniquely blocked.

We will now utilize this system to define the critical steps during synapse formation by reconstructing specific functions through molecular replacement.

Moreover, we will extend our previous discoveries of the proteins CA10/11 and their role in regulating a key heparan sulfate proteoglycan polysaccharide on synaptic adhesion molecules of Neurexin family.

Combining biochemistry and analysis of unique knockout mice, we will define their function at a defined synapse and role in the secretory pathway by combining genetic models and mass spectrometry.I will lead the project, which will mainly be carried out by a PhD-student and a post-doc that I mentor, with further expertise provided by key international collaborators.

This work will increase our knowledge of how synapses in our brain are molecularly assembled, and possibly identify mechanisms to restore synaptic imbalances in human disease.