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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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Confirmation of the MSN manic phenotype using an experimental replication of the most robust behavioral measure from previous research on this mouse strain, total locomotor activity.A) MSN mice display stable heightened locomotor activity relative the outbred strain. ***P<0.001. B) The probability density for MSN mouse total locomotor activity is bimodal, while the probability density for the control strain is unimodal. This leads us to the hypothesis that MSN mice may display behavioral bipolarism, a hypothesis that will be examined in future work.
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pone-0038128-g001: Confirmation of the MSN manic phenotype using an experimental replication of the most robust behavioral measure from previous research on this mouse strain, total locomotor activity.A) MSN mice display stable heightened locomotor activity relative the outbred strain. ***P<0.001. B) The probability density for MSN mouse total locomotor activity is bimodal, while the probability density for the control strain is unimodal. This leads us to the hypothesis that MSN mice may display behavioral bipolarism, a hypothesis that will be examined in future work.

Mentions: Locomotor activity defined by total distance traveled (Fig. 1.A) was significantly higher in MSN mice than in ICR mice (P-value = 7×10−7, Monte Carlo permutation test, nMSN = nICR = 19, Z = −4.24, B = 1×107). The probability density distribution for total distance travelled for MSN mice was bimodal whereas the probability density distribution for ICR mice was unimodal (Fig. 1.B). Since the MSN strain is almost completely inbred, we do not believe this bimodality is evidence of two separate populations within the MSN strain.


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

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

Confirmation of the MSN manic phenotype using an experimental replication of the most robust behavioral measure from previous research on this mouse strain, total locomotor activity.A) MSN mice display stable heightened locomotor activity relative the outbred strain. ***P<0.001. B) The probability density for MSN mouse total locomotor activity is bimodal, while the probability density for the control strain is unimodal. This leads us to the hypothesis that MSN mice may display behavioral bipolarism, a hypothesis that will be examined in future work.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038128-g001: Confirmation of the MSN manic phenotype using an experimental replication of the most robust behavioral measure from previous research on this mouse strain, total locomotor activity.A) MSN mice display stable heightened locomotor activity relative the outbred strain. ***P<0.001. B) The probability density for MSN mouse total locomotor activity is bimodal, while the probability density for the control strain is unimodal. This leads us to the hypothesis that MSN mice may display behavioral bipolarism, a hypothesis that will be examined in future work.
Mentions: Locomotor activity defined by total distance traveled (Fig. 1.A) was significantly higher in MSN mice than in ICR mice (P-value = 7×10−7, Monte Carlo permutation test, nMSN = nICR = 19, Z = −4.24, B = 1×107). The probability density distribution for total distance travelled for MSN mice was bimodal whereas the probability density distribution for ICR mice was unimodal (Fig. 1.B). Since the MSN strain is almost completely inbred, we do not believe this bimodality is evidence of two separate populations within the MSN strain.

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