Archive Page: Genes to cognition

The Genes to cognition group moved to the University of Edinburgh in November 2011. We are maintaining this page as a historical record of the group's research at the Sanger Institute. To find out the latest about the group's research, please visit the Genes to Cognition website.

The team, headed by Seth Grant, examines the effect of knocking out specific genetic functions on the molecular architecture of the synapse, the junction between adjacent nerve cells in the brain, in the mouse and relating this information back to man. Synapse junctions are large, complex molecular structures that perform important functions ranging from transmitting nerve impulses to decoding the patterns of electrical activity and translating that information into behaviour and memory. The team uses a broad integrated approach that draws on the many specialties of modern molecular genetics, from highly specific genetic manipulation techniques to complex computational programming and analysis of large quantities of data. Understanding how minor changes in gene sequence affect the molecules that comprise the synapse junction, will aid in the understanding of brain diseases such as Alzheimers, and of mental illnesses, such as schizophrenia.

[Benedict Campbell, Wellcome Images]

Background

The Grant laboratory

Synaptic MAGUK associated signalling complex.

Synaptic MAGUK associated signalling complex.

Perhaps the greatest biological challenge of the 21st century is to understand the mechanisms of human behaviour. This intellectual challenge is of enormous practical significance given the burden of brain disease on our community. The main goal of the Grant laboratory is to identify molecular mechanisms underlying behaviour and identify their involvement in disease.

The synapse, the junction between nerve cells, is the most important component of the nervous system. It not only transmits electrical information between neurons, but also is responsible for converting the electrical signals into biochemical changes of long term memory. Using proteomic methods, our laboratory and others have characterised the composition of synapses, which are made of 1-2000 proteins. These proteins are organised into multiprotein complexes that act as molecular machines.

Our research focuses on understanding the synapse and the multiprotein machines using an integrated set of experimental strategies including genome-wide and specific gene studies. We aim to understand the logic behind the complexity of molecular organisation of the synapse using these strategies, with an emphasis on large-scale methods that allows the function of many genes to be examined. The Genes to Cognition (G2C) Programme is a consortium of scientists studying a key set of synapse proteins found in neurotransmitter receptor complexes (NMDA Receptor Complex or MAGUK Associated Signaling Complex) using large-scale approaches (see G2C below).

The philosophy of the group is to tackle the problems of behaviour using an integrated strategy bringing together genetic, proteomic, biochemical, electrophysiological, neuroanatomical, behavioural and bioinformatic approaches. Central to this integrated approach is the creation of mice carrying defined mutations in genes encoding synaptic proteins using the techniques of homologous recombination in embryonic stem cells. The analysis of these mutants allows us to study the role of these proteins in synaptic function and behaviour as well as characterise the biochemical pathways affected by the mutations.

The integrative research environment of the group offers opportunities for training and collaboration for individuals with interests in specific technologies and a desire to learn about a broad range of approaches to understanding the brain. Students and PostDocs are encouraged to develop independent projects. For more information, please visit: http://www.genes2cognition.org/pressrelease/edinburgh_move.html.

Research

The Genes to cognition programme (G2C)

Synapse phosphoproteome network.

Synapse phosphoproteome network.

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The Genes to cognition (G2C) programme is a systematic integrative research program that bridges basic and clinical neuroscience and was initiated by support from the Wellcome Trust. G2C is an international consortium of scientists studying synaptic molecules and their role in behaviour and disease. The G2C Programme collects and integrates data in the areas of psychiatry, human and mouse psychology, cellular neurophysiology and cell biology, proteomics and biochemistry, molecular biology, human and mouse genetics and genomics.

The central theme of the G2C project is the study of multiprotein complexes, called NRC (NMDA Receptor Complex) or MASC (MAGUK Associated Signaling Complex), found at excitatory synapses in the mammalian brain. These complexes were isolated from a mouse brain and found to have a surprisingly large number of proteins (~185). Over 50 of these proteins have been implicated in human diseases. In experimental animal models such as the knockout mouse or drug studies there have been ~50 genes reported to alter the properties of synaptic plasticity and forms of behavioural plasticity. These behaviors include learning and memory, pain, visual and somatosensory plasticity amongst others. G2C scientists are conducting a systematic study of mutations and polymorphisms in mouse and human genes encoding postsynaptic proteins, and exploring how these genes influence a broad range of phenotypes, especially cognition.

G2C's modular consortium.

G2C's modular consortium.

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The G2C consortium has a modular architecture incorporating specific scientific disciplines or activities. These modules provide a natural way for collaborators to join the programme.

The connection between mouse and human genetics is central to the strategy. In brief, the human genetics involves clinical investigators interested in diseases of the brain for example cognitive disorders; mental retardation, Alzheimers, schizophrenia, bipolar disorder) and normal cognition for example cognitive ageing and individual differences). Human DNA samples are sequenced and analysed for the NRC/MASC genes and variants identified. Because of the extensive information on these molecules in the G2C program from basic science studies the human genetic variants can be rapidly evaluated.

The G2C analysis pipeline.

The G2C analysis pipeline.

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The study of the genes in mice typically involves the generation of knockout mice followed by the G2C phenotyping pipeline. This involves molecular, neuropathology, electrophysiological and behavioural phenotyping. The data and all reagents are made available to collaborators and widely distributed. One important vehicle for distribution of data is the G2Cdb.

Resources

G2Cdb: an integrative databases for synapse biology

The G2C program has created an integrative database that stores data from the G2C research and links multiple databases including human genetic, expression and proteomic databases. We curated a comprehensive database of mouse knockouts that have been studied in synaptic plasticity and a behaviour database. We aim to make these databases repositories for published data (curated manuscripts), data generated in the G2C program as well as place for data submission directly by external groups.

G2C Online: an Education programme on brain and disease

We recognise the importance of education on all aspects of the research program and rather than develop educational material after the research has been completed we are developing that material from the outset. The major collaborator in the educational program is the Dolan DNA Learning Centre at Cold Spring Harbor. They are developing an education website and materials for schools and colleges called G2C Online, which contains extensive information, videos and interviews that inform on all aspects of the G2C research program.

Selected publications

  • Characterization of the proteome, diseases and evolution of the human postsynaptic density.

    Bayés A, van de Lagemaat LN, Collins MO, Croning MD, Whittle IR, Choudhary JS and Grant SG

    Nature neuroscience 2011;14;1;19-21

  • Neurotransmitters drive combinatorial multistate postsynaptic density networks.

    Coba MP, Pocklington AJ, Collins MO, Kopanitsa MV, Uren RT, Swamy S, Croning MD, Choudhary JS and Grant SG

    Science signaling 2009;2;68;ra19

  • Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins.

    Fernández E, Collins MO, Uren RT, Kopanitsa MV, Komiyama NH, Croning MD, Zografos L, Armstrong JD, Choudhary JS and Grant SG

    Molecular systems biology 2009;5;269

  • A general basis for cognition in the evolution of synapse signaling complexes.

    Grant SG

    Cold Spring Harbor symposia on quantitative biology 2009;74;249-57

  • A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability.

    Zalfa F, Eleuteri B, Dickson KS, Mercaldo V, De Rubeis S, di Penta A, Tabolacci E, Chiurazzi P, Neri G, Grant SG and Bagni C

    Nature neuroscience 2007;10;5;578-87

  • Network activity-independent coordinated gene expression program for synapse assembly.

    Valor LM, Charlesworth P, Humphreys L, Anderson CN and Grant SG

    Proceedings of the National Academy of Sciences of the United States of America 2007;104;11;4658-63

  • Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies.

    Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P, Delgado JY, Komiyama NH, O'Dell TJ and Grant SG

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;10;2673-82

  • Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome.

    Collins MO, Husi H, Yu L, Brandon JM, Anderson CN, Blackstock WP, Choudhary JS and Grant SG

    Journal of neurochemistry 2006;97 Suppl 1;16-23

  • The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.

    Pocklington AJ, Cumiskey M, Armstrong JD and Grant SG

    Molecular systems biology 2006;2;2006.0023

  • Proteomic analysis of in vivo phosphorylated synaptic proteins.

    Collins MO, Yu L, Coba MP, Husi H, Campuzano I, Blackstock WP, Choudhary JS and Grant SG

    The Journal of biological chemistry 2005;280;7;5972-82

  • SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor.

    Komiyama NH, Watabe AM, Carlisle HJ, Porter K, Charlesworth P, Monti J, Strathdee DJ, O'Carroll CM, Martin SJ, Morris RG, O'Dell TJ and Grant SG

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2002;22;22;9721-32

  • Isolation of 2000-kDa complexes of N-methyl-D-aspartate receptor and postsynaptic density 95 from mouse brain.

    Husi H and Grant SG

    Journal of neurochemistry 2001;77;1;281-91

  • 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

    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

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

  • Peroral small-intestinal biopsy: experience with the hydraulic multiple biopsy instrument in routine clinical practice.

    Scott BB and Losowsky MS

    Gut 1976;17;9;740-3

Team

No team members listed

* quick link - http://q.sanger.ac.uk/gen2cog