Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness
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...
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Format: | Article |
Language: | English |
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Nature Publishing Group
2021-02-01
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Series: | Translational Psychiatry |
Online Access: | https://doi.org/10.1038/s41398-021-01256-3 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 Giles E. Hardingham Anthony C. Vernon David J. Porteous August B. Smit David J. Price J. Kirsty Millar |
spellingShingle |
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 Giles E. Hardingham Anthony C. Vernon David J. Porteous August B. Smit David J. Price J. Kirsty Millar Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness Translational Psychiatry |
author_facet |
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 Giles E. Hardingham Anthony C. Vernon David J. Porteous August B. Smit David J. Price J. Kirsty Millar |
author_sort |
Marion Bonneau |
title |
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness |
title_short |
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness |
title_full |
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness |
title_fullStr |
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness |
title_full_unstemmed |
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness |
title_sort |
functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts disc1 and confers increased risk of psychiatric illness |
publisher |
Nature Publishing Group |
series |
Translational Psychiatry |
issn |
2158-3188 |
publishDate |
2021-02-01 |
description |
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. |
url |
https://doi.org/10.1038/s41398-021-01256-3 |
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doaj-392e0db05f914e418b87d06cd79f30fb2021-02-21T12:48:01ZengNature Publishing GroupTranslational Psychiatry2158-31882021-02-0111111610.1038/s41398-021-01256-3Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illnessMarion Bonneau0Shane T. O’ Sullivan1Miguel A. Gonzalez-Lozano2Paul Baxter3Phillippe Gautier4Elena Marchisella5Neil R. Hardingham6Robert A. Chesters7Helen Torrance8David M. Howard9Maurits A. Jansen10Melanie McMillan11Yasmin Singh12Michel Didier13Frank Koopmans14Colin A. Semple15Andrew M. McIntosh16Hansjürgen Volkmer17Maarten Loos18Kevin Fox19Giles E. Hardingham20Anthony C. Vernon21David J. Porteous22August B. Smit23David J. Price24J. Kirsty Millar25Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of EdinburghCentre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of EdinburghDepartment of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU UniversityCentre for Discovery Brain Sciences, Hugh Robson Building, The University of EdinburghMRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of EdinburghSylics Synaptologics BVSchool of Biosciences, Museum Avenue, Cardiff UniversityDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonCentre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of EdinburghSocial, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College LondonEdinburgh Preclinical Imaging, The Chancellor’s Building, The University of EdinburghCentre for Reproductive Health, The Queen’s Medical Research Institute, The University of EdinburghCentre for Genomics and TranscriptomicsTranslational Sciences at SanofiDepartment of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU UniversityMRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of EdinburghDivision of Psychiatry, Kennedy Tower, The University of EdinburghDepartment of Molecular Biology, NMI Natural and Medical Sciences Institute at the University of TübingenSylics Synaptologics BVSchool of Biosciences, Museum Avenue, Cardiff UniversityCentre for Discovery Brain Sciences, Hugh Robson Building, The University of EdinburghDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonCentre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of EdinburghDepartment of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU UniversityCentre for Discovery Brain Sciences, Hugh Robson Building, The University of EdinburghCentre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine at the University of EdinburghAbstract 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.https://doi.org/10.1038/s41398-021-01256-3 |