G2C::Group Members

Professor Seth Grant

Seth Grant graduated from Sydney University with a Bachelor of Science (Medicine) degree based on research in respiratory neurophysiology with Dr. D.J.C. Read in 1980. He graduated with Bachelor of Medicine and Bachelor of Surgery with First Class Honours in 1994 and also conducted respiratory physiology research at the Royal Free Hospital London with Dr. S.W. Clarke in 1981 and 1983. From 1985-1989 he was a Postdoctoral Fellow at Cold Spring Harbor Laboratory (New York) with Dr. D.Hanahan studying transgenic mouse models of cancer and diabetes. Next as a research associate at the Howard Hughes Medical Institute and Centre for Neurobiology and Behavior at Columbia University (New York) he studied mouse genetic models of learning and memory with Dr. E.R. Kandel (Nobel Laureate in Medicine and Physiology, 2000). He established his laboratory at the Centre for Genome Research at Edinburgh University in 1994 and in 2000 was appointed Professor of Molecular Neuroscience in the Division of Neuroscience. In 2003 he was appointed Principal Investigator at the Wellcome Trust Sanger Institute in Cambridge and remained there until 2011, when he returned to Edinburgh University. He has held additional appointments including the John Cade Visiting Professor at Melbourne University (2005), Honorary Professorship at Cambridge University (2007 onward) and elected Fellow of the Royal Society of Edinburgh (2011).

The long-term aim is to understand the fundamental mechanisms of behaviour and how these mechanisms are involved in brain disease. The research has focussed on the study of genes and proteins that control the synapses between nerve cells. Multiprotein machines comprising many different protein components are responsible for basic innate and learned behaviours and dysfunction in many brain diseases. Recent work shows that these mechanisms are conserved between mice and humans opening new avenues for diagnosis and therapeutic discoveries. The Genes to Cognition research team (www.genes2cognition.org) has generated a large amount of data and tools that are freely available and an education and public understanding website (www.g2conline.org).

 

Key Publications

Over 150 publications over 30 years. Key publications with citations > 700 follow. [10862698] [1361685] [2162051] [9853749]

  • Proteomic analysis of NMDA receptor-adhesion protein signaling complexes.

    Husi H, Ward MA, Choudhary JS, Blackstock WP and Grant SG

    Centre for Genome Research, Centre for Neuroscience, University of Edinburgh, West Mains Road, Edinburgh EH9 3JQ, UK.

    N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.

    Nature neuroscience 2000;3;7;661-9

  • Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.

    Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RG, Morrison JH, O'Dell TJ and Grant SG

    Centre for Genome Research, University of Edinburgh, UK.

    Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.

    Funded by: Wellcome Trust

    Nature 1998;396;6710;433-9

  • Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice.

    Grant SG, O'Dell TJ, Karl KA, Stein PL, Soriano P and Kandel ER

    Center for Neurobiology and Behavior, Howard Hughes Medical Institute, College of Physicians and Surgeons, Columbia University, New York, NY 10032.

    Mice with mutations in four nonreceptor tyrosine kinase genes, fyn, src, yes, and abl, were used to study the role of these kinases in long-term potentiation (LTP) and in the relation of LTP to spatial learning and memory. All four kinases were expressed in the hippocampus. Mutations in src, yes, and abl did not interfere with either the induction or the maintenance of LTP. However, in fyn mutants, LTP was blunted even though synaptic transmission and two short-term forms of synaptic plasticity, paired-pulse facilitation and post-tetanic potentiation, were normal. In parallel with the blunting of LTP, fyn mutants showed impaired spatial learning, consistent with a functional link between LTP and learning. Although fyn is expressed at mature synapses, its lack of expression during development resulted in an increased number of granule cells in the dentate gyrus and of pyramidal cells in the CA3 region. Thus, a common tyrosine kinase pathway may regulate the growth of neurons in the developing hippocampus and the strength of synaptic plasticity in the mature hippocampus.

    Funded by: NIA NIH HHS: AG08702; NICHD NIH HHS: HD24875; NIMH NIH HHS: MH45923; ...

    Science (New York, N.Y.) 1992;258;5090;1903-10

  • Differential plasmid rescue from transgenic mouse DNAs into Escherichia coli methylation-restriction mutants.

    Grant SG, Jessee J, Bloom FR and Hanahan D

    Cold Spring Harbor Laboratory, NY 11724.

    Plasmids comprising transgene insertions in four lines of transgenic mice have been retrieved by plasmid rescue into a set of Escherichia coli strains with mutations in different members of the methylation-dependent restriction system (MDRS). Statistical analysis of plasmid rescue frequencies has revealed that the MDRS loci detect differential modifications of the transgene insertions among mouse lines that show distinctive patterns of transgene expression. Plasmids in mice that express hybrid insulin transgenes during development can be readily cloned into E. coli strains carrying mutations in two of the MDRS loci, mcrA and mcrB. In mice in which transgene expression is inappropriately delayed into adulthood, plasmids can only be cloned into E. coli that carry mutations in all known MDRS activities. Differential cloning frequencies in the presence or absence of the various methylation-dependent restriction genes represent a further way to distinguish regions of mammalian chromosomes. These multiply deficient E. coli strains will also facilitate the molecular cloning of modified chromosomal DNA.

    Proceedings of the National Academy of Sciences of the United States of America 1990;87;12;4645-9

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

Cookies Policy | Terms and Conditions. This site is hosted by Edinburgh University and the Genes to Cognition Programme.