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The ANK3 Bipolar Disorder Gene Regulates Psychiatric-Related Behaviors That Are Modulated by Lithium and Stress

  • Melanie P. Leussis
    Affiliations
    Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital

    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology
    Search for articles by this author
  • Erin M. Berry-Scott
    Affiliations
    Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital

    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology
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  • Mai Saito
    Affiliations
    Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital

    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology
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  • Hueihan Jhuang
    Affiliations
    Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology
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  • Georgius de Haan
    Affiliations
    Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital

    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology
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  • Ozan Alkan
    Affiliations
    RNA Interference Platform, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Catherine J. Luce
    Affiliations
    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology
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  • Jon M. Madison
    Affiliations
    Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital

    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology
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  • Pamela Sklar
    Affiliations
    Departments of Psychiatry, Neuroscience, and Genetics and Genomic Science, Mount Sinai School of Medicine, New York, New York
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  • Thomas Serre
    Affiliations
    Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, Rhode Island
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  • David E. Root
    Affiliations
    RNA Interference Platform, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Tracey L. Petryshen
    Correspondence
    Address correspondence to Tracey Petryshen, Ph.D., Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, 185 Cambridge Street, Boston, MA 02114
    Affiliations
    Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital

    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology
    Search for articles by this author
Published:December 12, 2012DOI:https://doi.org/10.1016/j.biopsych.2012.10.016

      Background

      Ankyrin 3 (ANK3) has been strongly implicated as a risk gene for bipolar disorder (BD) by recent genome-wide association studies of patient populations. However, the genetic variants of ANK3 contributing to BD risk and their pathological function are unknown.

      Methods

      To gain insight into the potential disease relevance of ANK3, we examined the function of mouse Ank3 in the regulation of psychiatric-related behaviors using genetic, neurobiological, pharmacological, and gene-environment interaction (G×E) approaches. Ank3 expression was reduced in mouse brain either by viral-mediated RNA interference or through disruption of brain-specific Ank3 in a heterozygous knockout mouse.

      Results

      RNA interference of Ank3 in hippocampus dentate gyrus induced a highly specific and consistent phenotype marked by decreased anxiety-related behaviors and increased activity during the light phase, which were attenuated by chronic treatment with the mood stabilizer lithium. Similar behavioral alterations of reduced anxiety and increased motivation for reward were also exhibited by Ank3+/– heterozygous mice compared with wild-type Ank3+/+ mice. Remarkably, the behavioral traits of Ank3+/– mice transitioned to depression-related features after chronic stress, a trigger of mood episodes in BD. Ank3+/– mice also exhibited elevated serum corticosterone, suggesting that reduced Ank3 expression is associated with elevated stress reactivity.

      Conclusions

      This study defines a new role for Ank3 in the regulation of psychiatric-related behaviors and stress reactivity that lends support for its involvement in BD and establishes a general framework for determining the disease relevance of genes implicated by patient genome-wide association studies.

      Key Words

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      References

        • Barnett J.H.
        • Smoller J.W.
        The genetics of bipolar disorder.
        Neuroscience. 2009; 164: 331-343
        • Bender R.E.
        • Alloy L.B.
        Life stress and kindling in bipolar disorder: Review of the evidence and integration with emerging biopsychosocial theories.
        Clin Psychol Rev. 2011; 31: 383-398
        • Langan C.
        • McDonald C.
        Neurobiological trait abnormalities in bipolar disorder.
        Mol Psychiatry. 2009; 14: 833-846
        • Lee K.W.
        • Woon P.S.
        • Teo Y.Y.
        • Sim K.
        Genome wide association studies (GWAS) and copy number variation (CNV) studies of the major psychoses: What have we learnt?.
        Neurosci Biobehav Rev. 2011; 36: 556-571
        • Sklar P.
        • Ripke S.
        • Scott L.J.
        • Andreassen O.A.
        • Cichon S.
        • Craddock N.
        • et al.
        Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
        Nat Genet. 2011; 43: 977-983
      1. Leussis M, Madison JM, Petryshen TL (2012): Ankyrin 3: Genetic association with bipolar disorder and relevance to disease pathophysiology. Biol Mood Anxiety Disord 2:18.

        • Ripke S.
        • Sanders A.R.
        • Kendler K.S.
        • Levinson D.F.
        • Sklar P.
        • Holmans P.A.
        • et al.
        Genome-wide association study identifies five new schizophrenia loci.
        Nat Genet. 2011; 43: 969-976
        • Ruberto G.
        • Vassos E.
        • Lewis C.M.
        • Tatarelli R.
        • Girardi P.
        • Collier D.
        • et al.
        The cognitive impact of the ANK3 risk variant for bipolar disorder: Initial evidence of selectivity to signal detection during sustained attention.
        PloS One. 2011; 6: e16671
        • Roussos P.
        • Giakoumaki S.G.
        • Georgakopoulos A.
        • Robakis N.K.
        • Bitsios P.
        The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males.
        Bipolar Disord. 2011; 13: 250-259
        • Roussos P.
        • Katsel P.
        • Davis K.L.
        • Bitsios P.
        • Giakoumaki S.G.
        • Jogia J.
        • et al.
        Molecular and genetic evidence for abnormalities in the nodes of Ranvier in schizophrenia.
        Arch Gen Psychiatry. 2011; 69: 7-15
        • Bennett V.
        • Lambert S.
        Physiological roles of axonal ankyrins in survival of premyelinated axons and localization of voltage-gated sodium channels.
        J Neurocytol. 1999; 28: 303-318
        • Zhou D.
        • Lambert S.
        • Malen P.L.
        • Carpenter S.
        • Boland L.M.
        • Bennett V.
        AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing.
        J Cell Biol. 1998; 143: 1295-1304
        • Ango F.
        • di Cristo G.
        • Higashiyama H.
        • Bennett V.
        • Wu P.
        • Huang Z.J.
        Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment.
        Cell. 2004; 119: 257-272
        • Paez-Gonzalez P.
        • Abdi K.
        • Luciano D.
        • Liu Y.
        • Soriano-Navarro M.
        • Rawlins E.
        • et al.
        Ank3-dependent SVZ niche assembly is required for the continued production of new neurons.
        Neuron. 2011; 71: 61-75
        • Koch I.
        • Schwarz H.
        • Beuchle D.
        • Goellner B.
        • Langegger M.
        • Aberle H.
        Drosophila ankyrin 2 is required for synaptic stability.
        Neuron. 2008; 58: 210-222
        • Pielage J.
        • Cheng L.
        • Fetter R.D.
        • Carlton P.M.
        • Sedat J.W.
        • Davis G.W.
        A presynaptic giant ankyrin stabilizes the NMJ through regulation of presynaptic microtubules and transsynaptic cell adhesion.
        Neuron. 2008; 58: 195-209
        • Crawley J.N.
        Behavioral phenotyping strategies for mutant mice.
        Neuron. 2008; 57: 809-818
        • Nestler E.J.
        • Hyman S.E.
        Animal models of neuropsychiatric disorders.
        Nat Neurosci. 2010; 13: 1161-1169
        • Joels M.
        • Karst H.
        • Alfarez D.
        • Heine V.M.
        • Qin Y.
        • van Riel E.
        • et al.
        Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus.
        Stress. 2004; 7: 221-231
        • Sahay A.
        • Drew M.R.
        • Hen R.
        Dentate gyrus neurogenesis and depression.
        Prog Brain Res. 2007; 163: 697-722
        • Ng W.X.
        • Lau I.Y.
        • Graham S.
        • Sim K.
        Neurobiological evidence for thalamic, hippocampal and related glutamatergic abnormalities in bipolar disorder: A review and synthesis.
        Neurosci Biobehav Rev. 2009; 33: 336-354
        • Boku S.
        • Nakagawa S.
        • Masuda T.
        • Nishikawa H.
        • Kato A.
        • Toda H.
        • et al.
        Effects of mood stabilizers on adult dentate gyrus-derived neural precursor cells.
        Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 111-117
        • Shim S.S.
        • Hammonds M.D.
        • Ganocy S.J.
        • Calabrese J.R.
        Effects of sub-chronic lithium treatment on synaptic plasticity in the dentate gyrus of rat hippocampal slices.
        Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31: 343-347
        • Murray G.
        • Harvey A.
        Circadian rhythms and sleep in bipolar disorder.
        Bipolar Disord. 2010; 12: 459-472
        • Jhuang H.
        • Garrote E.
        • Yu X.
        • Khilnani V.
        • Poggio T.
        • Steele A.D.
        • et al.
        Automated home-cage behavioural phenotyping of mice.
        Nat Commun. 2010; 1: 68
        • Zhang X.
        • Bennett V.
        Restriction of 480/270-kD ankyrin G to axon proximal segments requires multiple ankyrin G-specific domains.
        J Cell Biol. 1998; 142: 1571-1581
        • Daban C.
        • Vieta E.
        • Mackin P.
        • Young A.H.
        Hypothalamic-pituitary-adrenal axis and bipolar disorder.
        Psychiatr Clin North Am. 2005; 28: 469-480
        • Cryan J.F.
        • Holmes A.
        The ascent of mouse: Advances in modelling human depression and anxiety.
        Nat Rev Drug Discov. 2005; 4: 775-790
        • Blanchard R.J.
        • Nikulina J.N.
        • Sakai R.R.
        • McKittrick C.
        • McEwen B.
        • Blanchard D.C.
        Behavioral and endocrine change following chronic predatory stress.
        Physiol Behav. 1998; 63: 561-569
        • Flaisher-Grinberg S.
        • Einat H.
        Strain-specific battery of tests for domains of mania: Effects of valproate, lithium and imipramine.
        Front Psychiatry. 2010; 1: 10
        • Einat H.
        Different behaviors and different strains: Potential new ways to model bipolar disorder.
        Neurosci Biobehav Rev. 2007; 31: 850-857
        • Tronche F.
        • Kellendonk C.
        • Kretz O.
        • Gass P.
        • Anlag K.
        • Orban P.C.
        • et al.
        Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety.
        Nat Genet. 1999; 23: 99-103
        • Le-Niculescu H.
        • McFarland M.J.
        • Ogden C.A.
        • Balaraman Y.
        • Patel S.
        • Tan J.
        • et al.
        Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism.
        Am J Med Genet B Neuropsychiatr Genet. 2008; 147B: 134-166
        • Mukherjee S.
        • Coque L.
        • Cao J.L.
        • Kumar J.
        • Chakravarty S.
        • Asaithamby A.
        • et al.
        Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior.
        Biol Psychiatry. 2010; 68: 503-511
        • Dao D.T.
        • Mahon P.B.
        • Cai X.
        • Kovacsics C.E.
        • Blackwell R.A.
        • Arad M.
        • et al.
        Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans.
        Biol Psychiatry. 2010; 68: 801-810
        • Gould T.D.
        • Einat H.
        • O’Donnell K.C.
        • Picchini A.M.
        • Schloesser R.J.
        • Manji H.K.
        Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors.
        Neuropsychopharmacology. 2007; 32: 2173-2183
        • O’Brien W.T.
        • Harper A.D.
        • Jove F.
        • Woodgett J.R.
        • Maretto S.
        • Piccolo S.
        • et al.
        Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium.
        J Neurosci. 2004; 24: 6791-6798
        • Beaulieu J.M.
        • Marion S.
        • Rodriguiz R.M.
        • Medvedev I.O.
        • Sotnikova T.D.
        • Ghisi V.
        • et al.
        A beta-arrestin 2 signaling complex mediates lithium action on behavior.
        Cell. 2008; 132: 125-136
      2. Tapia M, Del Puerto A, Puime A, Sanchez-Ponce D, Fronzaroli-Molinieres L, Pallas-Bazarra N, et al. (2012): GSK3 and beta-catenin determines functional expression of sodium channels at the axon initial segment [published online ahead of print July 5]. Cell Mol Life Sci.

        • Saab B.J.
        • Georgiou J.
        • Nath A.
        • Lee F.J.
        • Wang M.
        • Michalon A.
        • et al.
        NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory.
        Neuron. 2009; 63: 643-656
        • Engin E.
        • Treit D.
        The role of hippocampus in anxiety: Intracerebral infusion studies.
        Behav Pharmacol. 2007; 18: 365-374
        • Gray J.A.
        • McNaughton N.
        The neuropsychology of anxiety: Reprise.
        Nebr Symp Motiv. 1996; 43: 61-134
        • Hirshfeld-Becker D.R.
        • Biederman J.
        • Faraone S.V.
        • Segool N.
        • Buchwald J.
        • Rosenbaum J.F.
        Lack of association between behavioral inhibition and psychosocial adversity factors in children at risk for anxiety disorders.
        Am J Psychiatry. 2004; 161: 547-555
        • Machado-Vieira R.
        • Manji H.K.
        • Zarate Jr, C.A.
        The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis.
        Bipolar Disord. 2009; 11: 92-109

      Linked Article

      • The Ups and Downs of Bipolar Disorder Research
        Biological PsychiatryVol. 73Issue 7
        • Preview
          Bipolar disorder is a debilitating disease that continues to thwart a tremendous effort to understand its pathogenesis. Consequently, new treatment development has also languished. However, some inroads have been achieved. The first of these was undoubtedly the discovery that lithium stabilizes mood in a significant portion of patients with bipolar disorder. Not only was lithium pivotal for the treatment of this severe psychiatric disorder, but it also provided a critical tool to examine responses in patients and laboratory animals to acquire clues about the etiology of bipolar disorder (Figure 1), as indeed it was used in two reports published in this issue of Biological Psychiatry (1,2).
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