The synaptome architecture of the mammalian brain

Synapses are the hallmark of brain complexity. Their constituent proteins are disrupted in over 130 brain diseases and are the targets of many therapeutic and abused drugs. Traditionally, synapses have been categorised based on neurotransmitters. A fundamentally new approach called synaptome mapping, which enables the molecular analysis of individual synapses on a whole-brain scale, reveals that synapses are far more diverse than previously known and distributed into a remarkable 3D architecture of the brain. The goal of this programme is to leverage synaptome mapping, in combination with complementary genetic, proteomic and cellular approaches, to comprehensively analyse synapse diversity and architecture across the major classes of mammalian brain synapses. This provides the missing link between existing and emerging synapse classifications that is crucial to full functional understanding. Within this comprehensive, integrated framework, our programme will encompass the impacts of ageing, environment, lived experience and mutations, uncovering the contribution of synapse diversity to regional and temporal vulnerabilities, resiliences and adaptation. These findings will inform new principles of brain architecture and function, with important implications across all areas from genetics to systems neuroscience, and will direct novel avenues for therapies aimed at treating a wide range of brain and behavioural disorders.