This award is sponsored by the EJN publisher Wiley and is given in recognition of an outstanding scientific work in any area of neuroscience. In 2020 the FENS EJN Award is presented to Prof. Seth Grant (University of Edinburgh, UK).
Seth Grant is internationally recognized for his seminal contributions to understanding the molecular biology of brain synapses and their function in health and disease. Pioneering work on the postsynaptic proteome (PSP) of excitatory synapses, spanning 25 years in the UK and involving major European and international partnerships, has produced transformative conceptual advances in our appreciation of brain structure and the mechanisms of learning, memory and behaviour, and revealed the key role of the synapse in numerous developmental, neurological and psychiatric diseases (synaptopathies), something promoted by a commitment to the dissemination and sharing of new findings.
His work (176 research publications to date) has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of proteins such as PSD95 and how these assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising PSPs in multiple species, including human and mouse, revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution and the establishment of vertebrate behavioural complexity.
His lab identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. His proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. He uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. He discovered the “Genetic Lifespan Calendar”, a genomic programme that could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults.
The Genes to Cognition programme is the largest genetic study undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. Seth has made important conceptual advances that inform how the repertoire of innate and learned behaviours is built from unique combinations of postsynaptic proteins that amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex and, consequently, why the phenotypes of synaptopathies are so diverse.
His most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. Next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain have revealed the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.
The FENS EJN Award is sponsored by Wiley (publisher of EJN) and was presented to Prof. Grant at the FENS Forum 2020 (11 – 15 July 2020).