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Ablation of Type III Adenylyl Cyclase in Mice Causes Reduced Neuronal Activity, Altered Sleep Pattern, and Depression-like Phenotypes

  • Xuanmao Chen
    Correspondence
    Address correspondence to: Xuanmao Chen, Ph.D., University of Washington, Department of Pharmacology, Health Sciences Building, Mail Box 357280, Seattle, WA 98195-7750.
    Affiliations
    Department of Pharmacology, University of Washington, Seattle, Washington

    Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire
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  • Author Footnotes
    1 JL is currently affiliated with the College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
    Jie Luo
    Footnotes
    1 JL is currently affiliated with the College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
    Affiliations
    Department of Pharmacology, University of Washington, Seattle, Washington
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  • Yihua Leng
    Affiliations
    Department of Pharmacology, University of Washington, Seattle, Washington
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  • Yimei Yang
    Affiliations
    Department of Pharmacology, University of Washington, Seattle, Washington
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  • Larry S. Zweifel
    Affiliations
    Department of Pharmacology, University of Washington, Seattle, Washington

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington
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  • Richard D. Palmiter
    Affiliations
    Howard Hughes Medical Institute, Department of Biochemistry, School of Medicine, University of Washington, Seattle, Washington
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  • Daniel R. Storm
    Affiliations
    Department of Pharmacology, University of Washington, Seattle, Washington
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  • Author Footnotes
    1 JL is currently affiliated with the College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
Published:December 18, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.12.012

      Abstract

      Background

      Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3; ADCY3) in MDD. Moreover, the expression level of AC3 in blood has been considered as a MDD biomarker in humans. Nevertheless, there is a lack of supporting evidence from animal studies.

      Methods

      We employed multiple approaches to experimentally evaluate if AC3 is a contributing factor for major depression using mouse models lacking the Adcy3 gene.

      Results

      We found that conventional AC3 knockout (KO) mice exhibited phenotypes associated with MDD in behavioral assays. Electroencephalography/electromyography recordings indicated that AC3 KO mice have altered sleep patterns characterized by increased percentage of rapid eye movement sleep. AC3 KO mice also exhibit neuronal atrophy. Furthermore, synaptic activity at cornu ammonis 3–cornu ammonis 1 synapses was significantly lower in AC3 KO mice, and they also exhibited attenuated long-term potentiation as well as deficits in spatial navigation. To confirm that these defects are not secondary responses to anosmia or developmental defects, we generated a conditional AC3 floxed mouse strain. This enabled us to inactivate AC3 function selectively in the forebrain and to inducibly ablate it in adult mice. Both AC3 forebrain-specific and AC3 inducible knockout mice exhibited prodepression phenotypes without anosmia.

      Conclusions

      This study demonstrates that loss of AC3 in mice leads to decreased neuronal activity, altered sleep pattern, and depression-like behaviors, providing strong evidence supporting AC3 as a contributing factor for MDD.

      Keywords

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      Linked Article

      • Depression and Adenylyl Cyclase: Sorting Out the Signals
        Biological PsychiatryVol. 80Issue 11
        • Preview
          The article in this issue of Biological Psychiatry by Chen et al. (1) suggests that knockout of adenylyl cyclase 3 (AC3—Adcy3) leads to depression. The study knocks out AC3 three ways: globally, targeted to forebrain, or conditionally. In a comprehensive series of behavioral studies, the data from this study reveal a “depressive” phenotype. This thorough and thoughtful study was undertaken, at least in part, pursuant to the suggestion that ADCY3 polymorphisms track with major depressive disorder (MDD).
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