Keynote Speaker: Dr. Seth Grant Wellcome Trust Sanger Institute, Cambridge, UK Synapse systems biology and the origins of the brain Synapses are a fundamental structure responsible for connecting neural networks and processing of information. The proteome of the synapse comprises 1-2000 proteins organised into multiprotein complexes with modular molecular network architecture. Proteomics reveals that postsynaptic neurotransmitter receptors are organised with 100-200 proteins embedded within the postsynaptic density (PSD). Synapse phosphoproteomics shows that the activation of glutamate and dopamine receptors drive networks of hundreds of proteins and phosphorylation sites that orchestrate the output on many classes of proteins. The combinations of outputs is driven by different patterns of synaptic activity and is responsible for forms of plasticity such as long-term potentiation and depression. These postsynaptic phosphoproteome networks include switching and regulatory components that result in a postsynaptic ‘computational’ system of extraordinary complexity and informational processing capacity. We have studied the origins and evolution of synapses and found that an ancestral protosynapse originating in unicellular animals predated the neuronal synapse of metazoans. The protosynapse was elaborated upon by the addition of specific classes of signaling proteins in metazoans and a further increase in complexity in chordates. The evolutionary expansion in synapse proteome complexity has contributed to the signaling networks and forms of plasticity found in higher species. Importantly, this complexity, which predated the evolution of the large regionalised brain of vertebrates, was exploited to provide novel neuronal types and synapses in different brain regions. Thus synapse proteome evolution are a template for the origins and complexity of nervous systems. The synapse proteome networks are a substrate for a wide variety of brain diseases. Disruption of individual genes and combinations of genes disrupt the organisation and signaling of postsynaptic complexes and networks. The networks are also a potential substrate for new therapeutic approaches.