Major disorders of the Central Nervous System (CNS) affect one in three people in the developed world, often seriously disable the affected individual, and together account for the single largest burden on the healthcare systems of the EU. Most of these disorders act at the neuronal synapse, a cellular organelle comprising in the order of 2000 proteins. Pleiotropy, cross-talk between proteins and the complexity of the underlying signalling complexes pose a significant challenge to dissecting the molecular mechanisms of disease and to design efficient drugs. SynSys assembles leading European laboratories to provide the expertise and established research platforms that uniquely enable a systems-level analysis of synaptic signalling. The consortium features a closed loop from data integration and modelling, human genetics, physiology, proteomics and the application of engineered model systems to test model predictions. The main objectives of this project are to (i) provide a qualitative and quantitative description of the protein composition and the interactome of the mammalian glutamatergic synapse that integrates known human variation in these genes, (ii) to generate quantitative dynamic models describing the main functional features of the synaptic system, (iii) to reiterate on modeling by relating model predictions to synaptic function, (iv) to identify and validate, using appropriate model systems, human vulnerability genes that may form the basis of future therapies. Only a Systems level analysis can provide the means to describe synaptic transmission from molecule to function, its dynamics in relation to physiology and, brain function and brain disorders. As such, SynSys will establish a new platform for iterative molecular analysis of synapse function and dynamic modeling, with the perspective to generate a blueprint for discovery of novel pathways and targets that enable rational strategies to design therapies for human brain disease.