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Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1–cAMP Response Element Binding–Brain-Derived Neurotrophic Factor Pathway

  • Author Footnotes
    1 BJ, HW, and J-LW contributed equally to this work.
    Bo Jiang
    Correspondence
    Address correspondence to Bo Jiang, M.D., Ph.D., Department of Pharmacology, School of Pharmacy, Nantong University, No. 19 QiXiu Road, Nantong 226001, Jiangsu, China.
    Footnotes
    1 BJ, HW, and J-LW contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
    Search for articles by this author
  • Author Footnotes
    1 BJ, HW, and J-LW contributed equally to this work.
    Hao Wang
    Footnotes
    1 BJ, HW, and J-LW contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
    Search for articles by this author
  • Author Footnotes
    1 BJ, HW, and J-LW contributed equally to this work.
    Jin-Liang Wang
    Footnotes
    1 BJ, HW, and J-LW contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
    Search for articles by this author
  • Ying-Jie Wang
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Qing Zhu
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Cheng-Niu Wang
    Affiliations
    Basic Medical Research Centre, Medical College, Nantong University, Nantong, Jiangsu, China
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  • Lu Song
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Ting-Ting Gao
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Yuan Wang
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Guo-Liang Meng
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Feng Wu
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Yong Ling
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Wei Zhang
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China

    Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
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  • Jun-Xu Li
    Correspondence
    Jun-Xu Li, M.D., Ph.D., Department of Pharmacology, School of Pharmacy, Nantong University, No. 19 QiXiu Road, Nantong 226001, Jiangsu, China.
    Affiliations
    Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China
    Search for articles by this author
  • Author Footnotes
    1 BJ, HW, and J-LW contributed equally to this work.

      Abstract

      Background

      Developing novel pharmacological targets beyond monoaminergic systems is now a popular strategy for finding new ways to treat depression. Salt-inducible kinase (SIK) is a kinase that regulates the nuclear translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator (CRTC) by phosphorylation. Here, we hypothesize that dysfunction of the central SIK-CRTC system may contribute to the pathogenesis of depression.

      Methods

      Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, viral-mediated gene transfer, Western blotting, coimmunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunohistochemistry were used in this study (for in vivo studies, n = 10; for in vitro studies, n = 5).

      Results

      Both CSDS and CUMS markedly increased the expression of hippocampal SIK2, which reduced CRTC1 nuclear translocation and binding of CRTC1 and CREB in the hippocampus. Genetic overexpression of hippocampal SIK2 in naïve mice simulated chronic stress, inducing depressive-like behaviors in the forced swim test, tail suspension test, sucrose preference test, and social interaction test, as well as decreasing the brain-derived neurotrophic factor signaling cascade and neurogenesis in the hippocampus. In contrast, genetic knockdown and knockout of hippocampal SIK2 protected against CSDS and CUMS, exerting significant antidepressant-like effects that were mediated via the downstream CRTC1-CREB–brain-derived neurotrophic factor pathway. Moreover, fluoxetine, venlafaxine, and mirtazapine all significantly restored the effects of CSDS and CUMS on the hippocampal SIK2-CRTC1 pathway, which was necessary for their antidepressant actions.

      Conclusions

      The hippocampal SIK2-CRTC1 pathway is involved in the pathogenesis of depression, and hippocampal SIK2 could be a novel target for the development of antidepressants.

      Keywords

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          Erratum to: “Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1–cAMP Response Element Binding–Brain-Derived Neurotrophic Factor Pathway,” by Jiang et al. (Biol Psychiatry 2019; 85: 650–666); 10.1016/j.biopsych.2018.10.004 .
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