Synapses are the fundamental processing elements that form the basis for the unsurpassed computational power of our brain. For many of the major brain disorders, both acute and age- dependent, pathogenesis can be traced back to synaptic dysfunction.

Synapses are complex, dynamic structures of approximately 1μm3 comprising around two thousand different types of proteins (excluding the synaptic mitochrondrial proteome and specific post-translational modifications). Considering this complexity, a systems biology analysis of the synapse, while challenging, is feasible with direct impact for our understanding of cognitive processes and for medical intervention in disorders. Synapse function can be studied in highly standardized, reduced preparations, which allows a multi-level quantitative systems analysis and integration of genomics, proteomics and (patho-)physiology. Quantitative functional (dynamic) models will be necessary to identify disease factors within protein networks that are not easily accessible using classical approaches. A quantitative understanding and computational modeling of networks opens essential new directions to assess and correct dysfunctional network performance and provides a blueprint for target discovery on the basis of a rational strategy to design therapies for human brain disease.
Background

Executive Summary of the Program
The overall aim of this program is to understand molecular function and plasticity of the synapse in health and disease. In order to do so, we aim at constructing protein interaction models (interactome) of the synapse that will be based on different conditions of synaptic function and on mouse knockouts of synaptic proteins. The synaptic interactome models will be based on quantitative experimental data, which ultimately explain how a complex protein network drives synaptic functions in the brain and predicts its adaptive capacities in response to environmental cues, such as behavioral challenges and pharmacological interventions. Finally, knowledge about synaptic function will be integrated to study synaptic networks in vitro and in vivo. Specific objectives are to provide targets for synaptic modulation and to dissect disease phenotypes by identifying crucial nodes and connectivity of the network.