Cargando…
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness
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 enrichme...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895946/ https://www.ncbi.nlm.nih.gov/pubmed/33608504 http://dx.doi.org/10.1038/s41398-021-01256-3 |
_version_ | 1783653459820544000 |
---|---|
author | Bonneau, Marion Sullivan, Shane T. O’ Gonzalez-Lozano, Miguel A. Baxter, Paul Gautier, Phillippe Marchisella, Elena Hardingham, Neil R. Chesters, Robert A. Torrance, Helen Howard, David M. Jansen, Maurits A. McMillan, Melanie Singh, Yasmin Didier, Michel Koopmans, Frank Semple, Colin A. McIntosh, Andrew M. Volkmer, Hansjürgen Loos, Maarten Fox, Kevin Hardingham, Giles E. Vernon, Anthony C. Porteous, David J. Smit, August B. Price, David J. Kirsty Millar, J. |
author_facet | Bonneau, Marion Sullivan, Shane T. O’ Gonzalez-Lozano, Miguel A. Baxter, Paul Gautier, Phillippe Marchisella, Elena Hardingham, Neil R. Chesters, Robert A. Torrance, Helen Howard, David M. Jansen, Maurits A. McMillan, Melanie Singh, Yasmin Didier, Michel Koopmans, Frank Semple, Colin A. McIntosh, Andrew M. Volkmer, Hansjürgen Loos, Maarten Fox, Kevin Hardingham, Giles E. Vernon, Anthony C. Porteous, David J. Smit, August B. Price, David J. Kirsty Millar, J. |
author_sort | Bonneau, Marion |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7895946 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78959462021-03-03 Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness Bonneau, Marion Sullivan, Shane T. O’ Gonzalez-Lozano, Miguel A. Baxter, Paul Gautier, Phillippe Marchisella, Elena Hardingham, Neil R. Chesters, Robert A. Torrance, Helen Howard, David M. Jansen, Maurits A. McMillan, Melanie Singh, Yasmin Didier, Michel Koopmans, Frank Semple, Colin A. McIntosh, Andrew M. Volkmer, Hansjürgen Loos, Maarten Fox, Kevin Hardingham, Giles E. Vernon, Anthony C. Porteous, David J. Smit, August B. Price, David J. Kirsty Millar, J. Transl Psychiatry Article 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. Nature Publishing Group UK 2021-02-19 /pmc/articles/PMC7895946/ /pubmed/33608504 http://dx.doi.org/10.1038/s41398-021-01256-3 Text en © The Author(s) 2021 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/. |
spellingShingle | Article Bonneau, Marion Sullivan, Shane T. O’ Gonzalez-Lozano, Miguel A. Baxter, Paul Gautier, Phillippe Marchisella, Elena Hardingham, Neil R. Chesters, Robert A. Torrance, Helen Howard, David M. Jansen, Maurits A. McMillan, Melanie Singh, Yasmin Didier, Michel Koopmans, Frank Semple, Colin A. McIntosh, Andrew M. Volkmer, Hansjürgen Loos, Maarten Fox, Kevin Hardingham, Giles E. Vernon, Anthony C. Porteous, David J. Smit, August B. Price, David J. Kirsty Millar, J. 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 | 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_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_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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895946/ https://www.ncbi.nlm.nih.gov/pubmed/33608504 http://dx.doi.org/10.1038/s41398-021-01256-3 |
work_keys_str_mv | AT bonneaumarion functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT sullivanshaneto functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT gonzalezlozanomiguela functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT baxterpaul functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT gautierphillippe functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT marchisellaelena functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT hardinghamneilr functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT chestersroberta functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT torrancehelen functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT howarddavidm functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT jansenmauritsa functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT mcmillanmelanie functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT singhyasmin functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT didiermichel functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT koopmansfrank functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT semplecolina functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT mcintoshandrewm functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT volkmerhansjurgen functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT loosmaarten functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT foxkevin functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT hardinghamgilese functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT vernonanthonyc functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT porteousdavidj functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT smitaugustb functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT pricedavidj functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness AT kirstymillarj functionalbraindefectsinamousemodelofachromosomalt111translocationthatdisruptsdisc1andconfersincreasedriskofpsychiatricillness |