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Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness

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Marion Bonneau, Shane T O' Sullivan, Miguel A Gonzalez-Lozano, Paul Baxter, Phillippe Gautier, Elena Marchisella, Neil R Hardingham, Robert A Chesters, Helen Torrance, David M Howard, Maurits A Jansen, Melanie McMillan, Yasmin Singh, Michel Didier, Frank Koopmans, Colin A Semple, Andrew M McIntosh, Hansjürgen Volkmer, Maarten Loos, Kevin Fox & 6 more Giles E Hardingham, Anthony C Vernon, David J Porteous, August B Smit, David J Price, J Kirsty Millar

Original languageEnglish
Article number135
Pages (from-to)135
JournalTranslational psychiatry
Volume11
Issue number1
DOIs
PublishedJun 2021

Bibliographical note

Funding Information: We thank the t(1:11) translocation family members who have taken part in our research by donating skin biopsies for reprogramming and production of neural cells. This work was funded by MRC grant MR/J004367/1, Brain & Behaviour Research Foundation Independent Investigator Grant 23306 and Young Investigator Grant 27404, European Union Seventh Framework Programme 607616FP7, Deciphering inter-and intracellular signalling in schizophrenia, a bequest from Eva Lester, Scottish Funding Council Scottish Senior Fellowship and Chief Scientists Office Senior Clinical fellowship Starter Grant awards to AMM, the University of Edinburgh Wellcome Trust Institutional Support Fund grant J22734, a Sir Henry Wellcome postdoctoral fellowship (213674/Z/18/Z) awarded to D.M.H., EUREKA/European Union Eurostars E! 7675 and an NWO Gravitation project: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.0212). Funding Information: The authors declare that they have no conflict of interests. A.M.M. has received research support from Eli Lilly and Company, Janssen and the Sackler Trust and speaker fees from Illumina and Janssen. A.C.V. has received research support from F. Hoffman La Roche and UCB Biopharma SPRL. M.L. is a full-time employee of Sylics (Synaptologics B.V.), a private company that offers mouse phenotyping services. A.B.S. is a shareholder of Alea Biotech B.V., a holding of Sylics (Synaptologics B.V.). M.D. is based at Sanofi. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.

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