A New Mouse Model for Mania Shares Genetic Correlates with Human Bipolar Disorder

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.

Inositol-Related Gene Knockouts Mimic Lithium’s Effect on Mitochondrial Function

“…No significantly differentially expressed gene sets were obtained in the Li-treatment groups, a result possibly related to the observation that Li treatment in humans affects diseased individuals much more than healthy subjects, corresponding to greater behavioral effects of the drug in challenged animals than animals under baseline conditions (Marchese et al, 2013;Saul et al, 2012).…”

Animal models of bipolar mania: The past, present and future

“…MSN mice display reduced anxiety and depression, increased sexual behavior, hyperactivity, and circadian abnormalities (Scotti et al, 2011, Saul et al, 2012, Saul et al, 2013). Lithium and olanzapine, an atypical antipsychotic, only reduced hyperactivity, with no changes observed for anxiety behavior in these mice (Scotti et al, 2011).…”

“…In addition to face and predictive validity, MSN mice may also have high construct validity. MSN mice share genetic correlates with BD (Saul et al, 2012). A number of transcripts show abnormal expression levels in hippocampus of MSN mice, many of which are previously associated with BD (Saul et al, 2012).…”

“…MSN mice share genetic correlates with BD (Saul et al, 2012). A number of transcripts show abnormal expression levels in hippocampus of MSN mice, many of which are previously associated with BD (Saul et al, 2012). For example, genes encoding proteins involved in chromatin packaging and remodeling are altered in MSN mice, such as Smarca4 , which has been implicated in neurodevelopmental disorders, including autism schizophrenia, and BD (Li et al, 2013).…”

Convergent functional genomics of psychiatric disorders

“…That work was subsequently extended to look at the gene expression changes in blood from the animals on the different treatments, as a way of identifying brain-blood biomarkers [Le-Niculescu et al, 2009b]. Niculescu et al, 2008Niculescu et al, , 2011b Nile grass rat [Ashkenazy-Frolinger et al, 2010] Methamphetamine [Niculescu et al, 2000;Macedo et al, 2013] Learned helplessness [Mingmalairak et al, 2010] CLOCK [Roybal et al, 2007;Mukherjee et al, 2010;Arey et al, 2013] Flinders Sensitive Line (FSL) rats [Malkesman and Weller, 2009] Methamphetamine/valproate [Ogden et al, 2004] Isolation housing [Le-Niculescu et al, 2008;Niwa et al, 2013] CTNNB1 [Gould et al, 2008] Wistar Kyoto (WKY) rats [Will et al, 2003;Malkesman and Weller, 2009] Amphetamine-chlordiazepoxide [Kelly et al, 2009] Forced swim test [Le-Niculescu et al, 2008] POLG [Kasahara et al, 2006;Kubota et al, 2010] Madison (MSN) [Saul et al, 2012] Lithium [Gould et al, 2007;Johnson et al, 2009;Kovacsics and Gould, 2010] Tail suspension test [Le-Niculescu et al, 2008] HINT1 [Barbier and Wang, 2009] Other mood stabilizers: Lamotrigene [Li et al, 2010], Topiramate [Bourin et al, 2009] Restraint stress [Johnson et al, 2009;Koo et al, 2010] GRIN2A [Taniguchi et al, 2009] Ouabain [Herman et al, 2007] Shock-induced aggression …”