We aim to understand how the structure and organisation of synapses in the brain, in particular the diversity of the postsynaptic proteome, informs the fundamental mechanisms of learning, memory and behaviour, how these processes change naturally during the lifespan, and how they go awry in neurological dysfunctions such as schizophrenia and Alzheimer’s disease.

Our current research is focussed on uncovering the scope, dynamics and functional impacts of synapse diversity throughout the brain, helping us to understand:

• the molecular mechanisms of innate and learned behaviour
• how information is stored and recalled in synapse diversity
• how the synaptome architecture of the brain changes throughout the lifespan
• the impacts of disease on the brain synaptome – synapse vulnerabilities and resilience

These studies are underpinned by on-going advances in the computational analysis of imaging data and the development of routes to integrate synaptomics among complementary brain ‘omics initiatives to maximize health discovery value.

• 1985 Postdoctoral Fellow with Douglas Hanahan, Cold Spring Harbor Laboratory
• 1989 Postdoctoral Fellow with Eric Kandel, Columbia University
• 1994 Reader, Centre for Genome Research, University of Edinburgh
• 2000 Professor of Molecular Neuroscience, University of Edinburgh
• 2003 Principal Investigator, Wellcome Trust Sanger Institute, Cambridge
• 2011 Professor of Molecular Neuroscience, University of Edinburgh
• Additional appointments (2005-2016): John Cade Visiting Professor, Florey Institute for Neuroscience and Mental Health, Melbourne, Australia; Honorary Professorship, University of Cambridge

Seth Grant is Professor of Molecular Neuroscience at the Centre for Clinical Brain Sciences, Edinburgh University, is affiliated with Simons Initiative for the Developing Brain and an Associate Member of the UK Dementia Research Institute. He is a Fellow of the Royal Society of Edinburgh (FRSE), Fellow of the Academy of Medical Sciences (FMedSci), and a Member of Academia Europaea (MAE). He established and leads the interdisciplinary Genes to Cognition Programme. His work on the genetics of cognition, synapse proteomics and synaptopathies has been recognised in prestigious national and international awards, most recently the 2019 IBANGS Distinguished Investigator Award and 2020 FENS EJN Award. He currently sits on the editorial board of five research journals in the neurosciences.

Prof. Grant has published over 200 research papers (My Bibliography: www.ncbi.nlm.nih.gov/myncbi/1Xsgr8ngRk-A7/bibliography/public/), nine of which have been cited over 1000 times among over 40,000 total citations (source: Google Scholar). Research in the Grant lab is funded by the Wellcome Trust, Medical Research Council, European Research Council, Simons Initiative for the Developing Brain, Chan Zuckerberg Initiative and Medical Research Scotland.

University of Sydney, Australia

Bachelor of Science Medicine (BSc Med), Medicine (MB), Surgery (BS)

Undergraduate: Neuroscience 3

Postgraduate: MSc by Research in Integrative Neuroscience

We study the genes and proteins that control synapses – the connections between nerve cells – with the long-term goal of understanding the fundamental mechanisms of behaviour. Multiprotein machines comprising many different synapse proteins are responsible for innate and learned behaviours, and their dysfunction underlies many brain diseases and neurological conditions, including Alzheimer’s disease, schizophrenia, autism, depression, addiction and intellectual disability. These mechanisms are conserved between mice and humans, opening new avenues for diagnosis and therapeutic discoveries.

Our current research is focussed on uncovering the scope and functional impacts of synapse diversity throughout the brain. We have developed methods for brain-wide mapping of protein composition at single-synapse resolution. These ‘synaptome’ maps, which reveal the molecular and morphological features of a billion synapses, have uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes. We have characterised how the synaptome architecture of the brain changes throughout the lifespan, with phases of rapid expansion followed by slow decline in old age that may inform on natural ageing and windows of disease susceptibility. Importantly, we have shown that mutations that cause cognitive disorders such as autism reorganise synaptome maps.

These new findings on synapse diversity have important implications for brain function in terms of learning and memory, leading to new models of how information is stored and recalled. We are now investigating the dynamics of the synaptome – the extent to which synapses change in the short term, during daily sleep cycles, and how rapidly synapse proteins are replaced; and, in the longer term, how sensory inputs from the environment and activity-dependent behaviour influence synaptome development. We are also unlocking brain complexity by characterising synapse diversity in the fundamental unit of the brain – the individual neuron. A major effort is progressing our laboratory, image analysis and computational tools to the direct study of the human brain, revealing the progressive impacts on the synaptome of dysfunctions such as Alzheimer’s disease. Synaptome mapping also has the potential to complement clinical techniques, uncovering what diagnostic imaging approaches such as PET and fMRI tell us about damage to the synaptome. A further key aim going forwards is to integrate all these synaptome data within existing large-scale international brain data resources to maximize their health discovery value.

Mouse Brain Synaptome Atlas - www.synaptome.genes2cognition.org

Mouse Lifespan Synaptome Atlas - www.brain-synaptome.org

Genes to Cognition research website and database - www.genes2cognition.org