G2C::Mice Resources

Genes to Cognition makes available the knock-out and transgenic mice lines generated as part of the research programme.

The mice listed below are available to interested researchers.

 

Available Mouse Lines (July 2013)

Colony Name Description Gene Affected Mutation Type PubMed ID Vector type Strain Available
Β-PIX Β-PIX knock-out Arhgef7 Null target C57BL/6J Request
CENTG2 CENTG2 knock-out Agap1 Null target C57BL/6J Request
CITRON CITRON knock-out Cit Null target C57BL/6J Request
CYFIP1 CYFIP1 knock-out Cyfip1 Null target C57BL/6J Request
CYFIP1 (flp) CYFIP1 conditional knock-out Cyfip1 Conditional Null target C57BL/6J Request
DREBRIN1 DREBRIN1 knock-out Dbn1 Null target C57BL/6J Request
DUSP7 DUSP7 knock-out Dusp7 Null target C57BL/6J Request
GKAP GKAP knock-out Dlgap1 Null target C57BL/6J Request
GKAP2 GKAP2 knock-out Dlgap2 Null target C57BL/6J Request
GKAP4 GKAP4 knock-out Dlgap4 Null trap C57BL/6J Request
GRIN1 GRIN1 knock-out Grin1 Null target C57BL/6J Request
GRIN1 (flp) GRIN1 conditional knock-out Grin1 Conditional Null target C57BL/6J Request
GRIT GRIT knock-out Arhgap32 Null trap C57BL/6J Request
MAGUIN-1 MAGUIN-1 knock-out Cnksr2 Null target C57BL/6J Request
NR2B-2ACTR NR2B C-terminal domain replaced with corresponding NR2A C-terminal domain Grin2b Knock-in [23201971] target C57BL/6J Request
NR2A-2BCTR NR2A C-terminal domain replaced with corresponding NR2B C-terminal domain Grin2a Knock-in [23201971] target C57BL/6J Request
PSD-93 PSD-93 knock-out Dlg2 Null [18936077] target C57BL/6J Request
PSD-95-GK PSD-95 guanylate kinase domain deletion, causing null Dlg4 Null [14980210] target C57BL/6J Request
SAP102 SAP102 knock-out Dlg3 Null [17344405] target C57BL/6J Request
SHANK2 SHANK2 knock-out Shank2 Null target C57BL/6J Request
SynGAP SynGAP knock-out Syngap1 Null [12427827] target C57BL/6J Request
TAP-PSD-95 TAP-tagged PSD-95 Dlg4 Knock-in [19455133] target C57BL/6J Request
TNiK TNIK knock-out Tnik Null [23035106] target C57BL/6J Request

 

References

  • Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior.

    Ryan TJ, Kopanitsa MV, Indersmitten T, Nithianantharajah J, Afinowi NO, Pettit C, Stanford LE, Sprengel R, Saksida LM, Bussey TJ, O'Dell TJ, Grant SG and Komiyama NH

    Genes to Cognition Programme, Wellcome Trust Sanger Institute, Cambridge, UK.

    Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C-terminal domains (CTDs). To identify shared ancestral functions and diversified subunit-specific functions, we exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock-in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit-specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long-term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 genes.

    Funded by: Medical Research Council: G0802238; NIMH NIH HHS: R01 MH060919; Wellcome Trust: 066717, 089703

    Nature neuroscience 2013;16;1;25-32

  • TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function.

    Coba MP, Komiyama NH, Nithianantharajah J, Kopanitsa MV, Indersmitten T, Skene NG, Tuck EJ, Fricker DG, Elsegood KA, Stanford LE, Afinowi NO, Saksida LM, Bussey TJ, O'Dell TJ and Grant SG

    Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, United Kingdom.

    Traf2 and NcK interacting kinase (TNiK) contains serine-threonine kinase and scaffold domains and has been implicated in cell proliferation and glutamate receptor regulation in vitro. Here we report its role in vivo using mice carrying a knock-out mutation. TNiK binds protein complexes in the synapse linking it to the NMDA receptor (NMDAR) via AKAP9. NMDAR and metabotropic receptors bidirectionally regulate TNiK phosphorylation and TNiK is required for AMPA expression and synaptic function. TNiK also organizes nuclear complexes and in the absence of TNiK, there was a marked elevation in GSK3β and phosphorylation levels of its cognate phosphorylation sites on NeuroD1 with alterations in Wnt pathway signaling. We observed impairments in dentate gyrus neurogenesis in TNiK knock-out mice and cognitive testing using the touchscreen apparatus revealed impairments in pattern separation on a test of spatial discrimination. Object-location paired associate learning, which is dependent on glutamatergic signaling, was also impaired. Additionally, TNiK knock-out mice displayed hyperlocomotor behavior that could be rapidly reversed by GSK3β inhibitors, indicating the potential for pharmacological rescue of a behavioral phenotype. These data establish TNiK as a critical regulator of cognitive functions and suggest it may play a regulatory role in diseases impacting on its interacting proteins and complexes.

    Funded by: Medical Research Council: G0802238; NIMH NIH HHS: MH609197, R01 MH060919; Wellcome Trust: 066717

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2012;32;40;13987-99

  • 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

    Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Cambridge, UK.

    The molecular complexity of mammalian proteomes demands new methods for mapping the organization of multiprotein complexes. Here, we combine mouse genetics and proteomics to characterize synapse protein complexes and interaction networks. New tandem affinity purification (TAP) tags were fused to the carboxyl terminus of PSD-95 using gene targeting in mice. Homozygous mice showed no detectable abnormalities in PSD-95 expression, subcellular localization or synaptic electrophysiological function. Analysis of multiprotein complexes purified under native conditions by mass spectrometry defined known and new interactors: 118 proteins comprising crucial functional components of synapses, including glutamate receptors, K+ channels, scaffolding and signaling proteins, were recovered. Network clustering of protein interactions generated five connected clusters, with two clusters containing all the major ionotropic glutamate receptors and one cluster with voltage-dependent K+ channels. Annotation of clusters with human disease associations revealed that multiple disorders map to the network, with a significant correlation of schizophrenia within the glutamate receptor clusters. This targeted TAP tagging strategy is generally applicable to mammalian proteomics and systems biology approaches to disease.

    Funded by: Wellcome Trust

    Molecular systems biology 2009;5;269

  • Opposing effects of PSD-93 and PSD-95 on long-term potentiation and spike timing-dependent plasticity.

    Carlisle HJ, Fink AE, Grant SG and O'Dell TJ

    Department of Physiology, David Geffen School of Medicine at UCLA, 53-231 Center for the Health Sciences, Box 951751, Los Angeles, CA 90095-1751, USA.

    The membrane-associated guanylate kinases (MAGUKs) PSD-95, PSD-93 and SAP102 are thought to have crucial roles in both AMPA receptor trafficking and formation of NMDA receptor-associated signalling complexes involved in synaptic plasticity. While PSD-95, PSD-93, and SAP102 appear to have similar roles in AMPA receptor trafficking, it is not known whether these MAGUKs also have functionally similar roles in synaptic plasticity. To explore this issue we examined several properties of basal synaptic transmission in the hippocampal CA1 region of PSD-93 and PSD-95 mutant mice and compared the ability of a number of different synaptic stimulation protocols to induce long-term potentiation (LTP) and long-term depression (LTD) in these mutants. We find that while both AMPA and NMDA receptor-mediated synaptic transmission are normal in PSD-93 mutants, PSD-95 mutant mice exhibit clear deficits in AMPA receptor-mediated transmission. Moreover, in contrast to the facilitation of LTP induction and disruption of LTD observed in PSD-95 mutant mice, PSD-93 mutant mice exhibit deficits in LTP and normal LTD. Our results suggest that PSD-95 has a unique role in AMPA receptor trafficking at excitatory synapses in the hippocampus of adult mice and indicate that PSD-93 and PSD-95 have essentially opposite roles in LTP, perhaps because these MAGUKs form distinct NMDA receptor signalling complexes that differentially regulate the induction of LTP by different patterns of synaptic activity.

    Funded by: NIMH NIH HHS: MH609197; Wellcome Trust

    The Journal of physiology 2008;586;24;5885-900

  • 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

    Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.

    Understanding the mechanisms whereby information encoded within patterns of action potentials is deciphered by neurons is central to cognitive psychology. The multiprotein complexes formed by NMDA receptors linked to synaptic membrane-associated guanylate kinase (MAGUK) proteins including synapse-associated protein 102 (SAP102) and other associated proteins are instrumental in these processes. Although humans with mutations in SAP102 show mental retardation, the physiological and biochemical mechanisms involved are unknown. Using SAP102 knock-out mice, we found specific impairments in synaptic plasticity induced by selective frequencies of stimulation that also required extracellular signal-regulated kinase signaling. This was paralleled by inflexibility and impairment in spatial learning. Improvement in spatial learning performance occurred with extra training despite continued use of a suboptimal search strategy, and, in a separate nonspatial task, the mutants again deployed a different strategy. Double-mutant analysis of postsynaptic density-95 and SAP102 mutants indicate overlapping and specific functions of the two MAGUKs. These in vivo data support the model that specific MAGUK proteins couple the NMDA receptor to distinct downstream signaling pathways. This provides a mechanism for discriminating patterns of synaptic activity that lead to long-lasting changes in synaptic strength as well as distinct aspects of cognition in the mammalian nervous system.

    Funded by: NIMH NIH HHS: R01 MH060919, R01 MH060919-10; Wellcome Trust: WT077155

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

  • Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity.

    Yao WD, Gainetdinov RR, Arbuckle MI, Sotnikova TD, Cyr M, Beaulieu JM, Torres GE, Grant SG and Caron MG

    Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.

    To identify the molecular mechanisms underlying psychostimulant-elicited plasticity in the brain reward system, we undertook a phenotype-driven approach using genome-wide microarray profiling of striatal transcripts from three genetic and one pharmacological mouse models of psychostimulant or dopamine supersensitivity. A small set of co-affected genes was identified. One of these genes encoding the synaptic scaffolding protein PSD-95 is downregulated in the striatum of all three mutants and in chronically, but not acutely, cocaine-treated mice. At the synaptic level, enhanced long-term potentiation (LTP) of the frontocortico-accumbal glutamatergic synapses correlates with PSD-95 reduction in every case. Finally, targeted deletion of PSD-95 in an independent line of mice enhances LTP, augments the acute locomotor-stimulating effects of cocaine, but leads to no further behavioral plasticity in response to chronic cocaine. Our findings uncover a previously unappreciated role of PSD-95 in psychostimulant action and identify a molecular and cellular mechanism shared between drug-related plasticity and learning.

    Funded by: NIDA NIH HHS: DA13511

    Neuron 2004;41;4;625-38

  • 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

    Division of Neuroscience, University of Edinburgh, Edinburgh EH8-9JZ, United Kingdom.

    At excitatory synapses, the postsynaptic scaffolding protein postsynaptic density 95 (PSD-95) couples NMDA receptors (NMDARs) to the Ras GTPase-activating protein SynGAP. The close association of SynGAP and NMDARs suggests that SynGAP may have an important role in NMDAR-dependent activation of Ras signaling pathways, such as the MAP kinase pathway, and in synaptic plasticity. To explore this issue, we examined long-term potentiation (LTP), p42 MAPK (ERK2) signaling, and spatial learning in mice with a heterozygous null mutation of the SynGAP gene (SynGAP(-/+)). In SynGAP(-/+) mutant mice, the induction of LTP in the hippocampal CA1 region was strongly reduced in the absence of any detectable alteration in basal synaptic transmission and NMDAR-mediated synaptic currents. Although basal levels of activated ERK2 were elevated in hippocampal extracts from SynGAP(-/+) mice, NMDAR stimulation still induced a robust increase in ERK activation in slices from SynGAP(-/+) mice. Thus, although SynGAP may regulate the ERK pathway, its role in LTP most likely involves additional downstream targets. Consistent with this, the amount of potentiation induced by stimulation protocols that induce an ERK-independent form of LTP were also significantly reduced in slices from SynGAP(-/+) mice. An elevation of basal phospho-ERK2 levels and LTP deficits were also observed in SynGAP(-/+)/H-Ras(-)/- double mutants, suggesting that SynGAP may normally regulate Ras isoforms other than H-Ras. A comparison of SynGAP and PSD-95 mutants suggests that PSD-95 couples NMDARs to multiple downstream signaling pathways with very different roles in LTP and learning.

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

© 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).

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