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

Saul MC, Gessay GM, Gammie SC - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. csaul@wisc.edu

ABSTRACT
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.

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RT-qPCR confirmation results for seven genes from the microarray.Ratio distribution is graphed as a box-and-whiskers plot. Ratios greater than 1 represent genes with higher expression in the MSN strain and ratios less than 1 represent genes with lower expression in the MSN strain relative to the ICR strain. *P<0.05; **P<0.01; ***P<0.001.
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pone-0038128-g003: RT-qPCR confirmation results for seven genes from the microarray.Ratio distribution is graphed as a box-and-whiskers plot. Ratios greater than 1 represent genes with higher expression in the MSN strain and ratios less than 1 represent genes with lower expression in the MSN strain relative to the ICR strain. *P<0.05; **P<0.01; ***P<0.001.

Mentions: We confirmed the results of seven genes from our microarray experiments using RT-qPCR. We chose genes for confirmation with an emphasis on gene products that we thought were either related to neural signaling pathways it would be possible to target pharmacologically or genes we could use as dependent variables in the future. We tested Cat (P-value = 0.001, expression ratio = 1.202), Cmklr1 (P-value<0.001, expression ratio = 1.404), Epor (P-value<0.001, expression ratio = 1.370), Fhit (P-value<0.001, expression ratio = 0.446), Npsr1 (P-value = 0.021, expression ratio = 2.426), P2rx7 (P-value = 0.006, expression ratio = 0.681), and Tac1 (P-value = 0.001, expression ratio = 0.696). The results of the RT-qPCR confirmation are shown in Fig. 3. All seven genes we chose to confirm were found significantly dysregulated in the same direction and at the same approximate magnitude as in the results of the microarray experiment. Altogether, our RT-qPCR confirmation provides evidence that our microarray data are fundamentally sound.


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

Saul MC, Gessay GM, Gammie SC - PLoS ONE (2012)

RT-qPCR confirmation results for seven genes from the microarray.Ratio distribution is graphed as a box-and-whiskers plot. Ratios greater than 1 represent genes with higher expression in the MSN strain and ratios less than 1 represent genes with lower expression in the MSN strain relative to the ICR strain. *P<0.05; **P<0.01; ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366954&req=5

pone-0038128-g003: RT-qPCR confirmation results for seven genes from the microarray.Ratio distribution is graphed as a box-and-whiskers plot. Ratios greater than 1 represent genes with higher expression in the MSN strain and ratios less than 1 represent genes with lower expression in the MSN strain relative to the ICR strain. *P<0.05; **P<0.01; ***P<0.001.
Mentions: We confirmed the results of seven genes from our microarray experiments using RT-qPCR. We chose genes for confirmation with an emphasis on gene products that we thought were either related to neural signaling pathways it would be possible to target pharmacologically or genes we could use as dependent variables in the future. We tested Cat (P-value = 0.001, expression ratio = 1.202), Cmklr1 (P-value<0.001, expression ratio = 1.404), Epor (P-value<0.001, expression ratio = 1.370), Fhit (P-value<0.001, expression ratio = 0.446), Npsr1 (P-value = 0.021, expression ratio = 2.426), P2rx7 (P-value = 0.006, expression ratio = 0.681), and Tac1 (P-value = 0.001, expression ratio = 0.696). The results of the RT-qPCR confirmation are shown in Fig. 3. All seven genes we chose to confirm were found significantly dysregulated in the same direction and at the same approximate magnitude as in the results of the microarray experiment. Altogether, our RT-qPCR confirmation provides evidence that our microarray data are fundamentally sound.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. csaul@wisc.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus