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      DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness

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      1 , 2 , 1 , 1 , 3 , 1 , 1 , 4 , 1 , 1 , 1 , 1 , 5 , 1 , 1 , 1 , 1 , 3 , 3 , 1 , 1 , 6 , 7 , 1 , 7 , 8 , 7 , 7 , 3 , 1 , 9 , 5 , 7 , 10 , 11 , 1 , 1 ,
      Translational Psychiatry
      Nature Publishing Group UK

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          Abstract

          The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of the translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether, our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.

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          Most cited references40

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          The postsynaptic organization of synapses.

          The postsynaptic side of the synapse is specialized to receive the neurotransmitter signal released from the presynaptic terminal and transduce it into electrical and biochemical changes in the postsynaptic cell. The cardinal functional components of the postsynaptic specialization of excitatory and inhibitory synapses are the ionotropic receptors (ligand-gated channels) for glutamate and γ-aminobutyric acid (GABA), respectively. These receptor channels are concentrated at the postsynaptic membrane and embedded in a dense and rich protein network comprised of anchoring and scaffolding molecules, signaling enzymes, cytoskeletal components, as well as other membrane proteins. Excitatory and inhibitory postsynaptic specializations are quite different in molecular organization. The postsynaptic density of excitatory synapses is especially complex and dynamic in composition and regulation; it contains hundreds of different proteins, many of which are required for cognitive function and implicated in psychiatric illness.
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            Engineering of a monomeric green-to-red photoactivatable fluorescent protein induced by blue light.

            Green fluorescent protein (GFP) and GFP-like proteins represent invaluable genetically encoded fluorescent probes. In the last few years a new class of photoactivatable fluorescent proteins (PAFPs) capable of pronounced light-induced spectral changes have been developed. Except for tetrameric KFP1 (ref. 4), all known PAFPs, including PA-GFP, Kaede, EosFP, PS-CFP, Dronpa, PA-mRFP1 and KikGR require light in the UV-violet spectral region for activation through one-photon excitation--such light can be phototoxic to some biological systems. Here, we report a monomeric PAFP, Dendra, derived from octocoral Dendronephthya sp. and capable of 1,000- to 4,500-fold photoconversion from green to red fluorescent states in response to either visible blue or UV-violet light. Dendra represents the first PAFP, which is simultaneously monomeric, efficiently matures at 37 degrees C, demonstrates high photostability of the activated state, and can be photoactivated by a common, marginally phototoxic, 488-nm laser line. We demonstrate the suitability of Dendra for protein labeling and tracking to quantitatively study dynamics of fibrillarin and vimentin in mammalian cells.
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              Long-Term Potentiation: From CaMKII to AMPA Receptor Trafficking.

              For more than 20 years, we have known that Ca(2+)/calmodulin-dependent protein kinase (CaMKII) activation is both necessary and sufficient for the induction of long-term potentiation (LTP). During this time, tremendous effort has been spent in attempting to understand how CaMKII activation gives rise to this phenomenon. Despite such efforts, there is much to be learned about the molecular mechanisms involved in LTP induction downstream of CaMKII activation. In this review, we highlight recent developments that have shaped our current thinking about the molecular mechanisms underlying LTP and discuss important questions that remain in the field.
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                Author and article information

                Contributors
                +44 (0)131 651 8732 , kirsty.millar@igmm.ed.ac.uk
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                6 September 2018
                6 September 2018
                2018
                : 8
                : 184
                Affiliations
                [1 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Genomic and Experimental Medicine, , MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, ; Edinburgh, UK
                [2 ]Xtuit Pharmaceuticals, Waltham, MA USA
                [3 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, MRC Human Genetics Unit, , MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, ; Edinburgh, UK
                [4 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Molecular Pharmacology Group, Wolfson Building, Institute of Neuroscience and Psychology, , The University of Glasgow, University Avenue, ; Glasgow, UK
                [5 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Regenerative Medicine, , The University of Edinburgh, ; Edinburgh, UK
                [6 ]Translational In Vivo Models at Sanofi, Frankfurt, Germany
                [7 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Division of Psychiatry, , The University of Edinburgh, ; Edinburgh, UK
                [8 ]ISNI 0000 0004 0472 2713, GRID grid.418961.3, Regeneron Pharmaceuticals, ; Tarrytown NY, USA
                [9 ]Translational Sciences at Sanofi, Chilly-Mazarin, France
                [10 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Integrative Physiology, , The University of Edinburgh, ; Edinburgh, UK
                [11 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, School of Cancer and Pharmaceutical Sciences, , King’s College London, ; London, UK
                Author information
                http://orcid.org/0000-0002-8398-0862
                http://orcid.org/0000-0002-2444-5675
                http://orcid.org/0000-0002-4076-9346
                http://orcid.org/0000-0002-0198-4588
                http://orcid.org/0000-0003-1249-6106
                Article
                228
                10.1038/s41398-018-0228-1
                6127284
                29317594
                dd1d7c9b-d015-4266-9d4a-b6f89ab34309
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 June 2018
                : 16 July 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000265, Medical Research Council (MRC);
                Award ID: G0902166
                Award ID: MR/J004367/1
                Award ID: G0902166
                Award ID: G0902166
                Award ID: MR/J004367/1
                Award ID: G0902166
                Award ID: MR/J0043567/1
                Award ID: MR/J004367/1
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000874, Brain and Behavior Research Foundation (Brain & Behavior Research Foundation);
                Award ID: 23306
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004963, EC | Seventh Framework Programme (European Union Seventh Framework Programme);
                Award ID: 607616FP7
                Award Recipient :
                Funded by: Wellcome Trust University of Edinburgh Strategic Support Fund
                Funded by: FundRef https://doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: WT/100135/Z/12/Z
                Award Recipient :
                Categories
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                © The Author(s) 2018

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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