Synapses participate in all our thoughts and actions and are damaged in over 100 genetic brain disorders. Synapses are the hallmark of brain complexity, being present in vast numbers and containing thousands of different proteins. Unravelling this complexity to get at the functional logic embedded within is a major challenge in neuroscience. We recently characterised excitatory synapse molecular diversity across the whole mammalian brain, revealing a remarkable 3D organisation of synapse types across the different regions – the ‘synaptome architecture’. This architecture is reorganised in genetic diseases, is important in structural and functional connectivity across the brain, and provides a mechanism for the storage and recall of information. But what of the fundamental, functional cellular building block of this architecture – the single neuron and its dendritic tree? Crucially, very little is known about the distribution of synapse types on individual neurons and what this actually means for brain function. The overarching goal of SYNAPTOME is to define single-neuron synaptome architecture (SNSA). We will develop new genetic labelling and computational approaches to systematically map SNSA in the mouse brain. We will identify the SNSA of specific functional types of neurons and determine whether neurons share a canonical SNSA. We will reveal how the SNSA is built during development and how it is relevant to the connections between neurons and their physiological properties and functional output. We will ask if the SNSA can direct us to the specific synapses damaged in genetic disorders. These studies will uncover fundamental design principles inherent in the building blocks of the brain that link genome, proteome and synaptome with the architecture and function of individual neurons and their organisation into brain-wide networks. The new tools, resources and knowledge that SYNAPTOME will bring will have wide application in neuroscience and disease research.
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