A new mouse model for mania shares genetic correlates with human bipolar disorder.

Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally...

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Main Authors: Michael C Saul, Griffin M Gessay, Stephen C Gammie
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2012-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3366954?pdf=render
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spelling doaj-96bc60ac163f48b2bdec1f4434a245d62020-11-25T00:23:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0176e3812810.1371/journal.pone.0038128A new mouse model for mania shares genetic correlates with human bipolar disorder.Michael C SaulGriffin M GessayStephen C GammieBipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.http://europepmc.org/articles/PMC3366954?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Michael C Saul
Griffin M Gessay
Stephen C Gammie
spellingShingle Michael C Saul
Griffin M Gessay
Stephen C Gammie
A new mouse model for mania shares genetic correlates with human bipolar disorder.
PLoS ONE
author_facet Michael C Saul
Griffin M Gessay
Stephen C Gammie
author_sort Michael C Saul
title A new mouse model for mania shares genetic correlates with human bipolar disorder.
title_short A new mouse model for mania shares genetic correlates with human bipolar disorder.
title_full A new mouse model for mania shares genetic correlates with human bipolar disorder.
title_fullStr A new mouse model for mania shares genetic correlates with human bipolar disorder.
title_full_unstemmed A new mouse model for mania shares genetic correlates with human bipolar disorder.
title_sort new mouse model for mania shares genetic correlates with human bipolar disorder.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2012-01-01
description Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.
url http://europepmc.org/articles/PMC3366954?pdf=render
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