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Metabotropic Glutamate Receptor 5 in Amygdala Target Neurons Regulates Susceptibility to Chronic Social Stress

  • Author Footnotes
    1 JK and SK contributed equally to this work.
    Jeongseop Kim
    Footnotes
    1 JK and SK contributed equally to this work.
    Affiliations
    Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, Republic of Korea

    Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
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  • Author Footnotes
    1 JK and SK contributed equally to this work.
    Shinwoo Kang
    Footnotes
    1 JK and SK contributed equally to this work.
    Affiliations
    Department of Pharmacology, College of Medicine, Gachon University, Incheon, Republic of Korea

    Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea

    Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea

    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
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  • Tae-Yong Choi
    Affiliations
    Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
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  • Author Footnotes
    2 K-AC and JWK contributed equally to this work.
    Keun-A Chang
    Correspondence
    Address correspondence to Keun-A Chang, Ph.D.
    Footnotes
    2 K-AC and JWK contributed equally to this work.
    Affiliations
    Department of Pharmacology, College of Medicine, Gachon University, Incheon, Republic of Korea

    Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea

    Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    2 K-AC and JWK contributed equally to this work.
    Ja Wook Koo
    Correspondence
    Ja Wook Koo, Ph.D.
    Footnotes
    2 K-AC and JWK contributed equally to this work.
    Affiliations
    Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, Republic of Korea

    Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    1 JK and SK contributed equally to this work.
    2 K-AC and JWK contributed equally to this work.

      Abstract

      Background

      Metabotropic glutamate receptor 5 (mGluR5) has been implicated in stress-related psychiatric disorders, particularly major depressive disorder. Although growing evidence supports the proresilient role of mGluR5 in corticolimbic circuitry in the depressive-like behaviors following chronic stress exposure, the underlying neural mechanisms, including circuits and molecules, remain unknown.

      Methods

      We measured the c-Fos expression and probability of neurotransmitter release in and from basolateral amygdala (BLA) neurons projecting to the medial prefrontal cortex (mPFC) and to the ventral hippocampus (vHPC) after chronic social defeat stress. The role of BLA projections in depressive-like behaviors was assessed using optogenetic manipulations, and the underlying molecular mechanisms of mGluR5 and downstream signaling were investigated by Western blotting, viral-mediated gene transfer, and pharmacological manipulations.

      Results

      Chronic social defeat stress disrupted neural activity and glutamatergic transmission in both BLA projections. Optogenetic activation of BLA projections reversed the detrimental effects of chronic social defeat stress on depressive-like behaviors and mGluR5 expression in the mPFC and vHPC. Conversely, inhibition of BLA projections of mice undergoing subthreshold social defeat stress induced a susceptible phenotype and mGluR5 reduction. These two BLA circuits appeared to act in an independent way. We demonstrate that mGluR5 overexpression in the mPFC or vHPC was proresilient while the mGluR5 knockdown was prosusceptible and that the proresilient effects of mGluR5 are mediated through distinctive downstream signaling pathways in the mPFC and vHPC.

      Conclusions

      These findings identify mGluR5 in the mPFC and vHPC that receive BLA inputs as a critical mediator of stress resilience, highlighting circuit-specific signaling for depressive-like behaviors.

      Keywords

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      • Metabotropic Glutamate Receptor 5: A Potential Molecular Switch and Beyond
        Biological PsychiatryVol. 92Issue 2
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          Depression is one of the most common mental illnesses, and it poses a serious threat to human health and well-being. Conventional antidepressants have substantial variations in clinical treatment efficacy, and despite the U.S. Food and Drug Administration’s approval of esketamine for treatment-resistant depression, further fast-acting and effective therapies are urgently needed. Recent clinical and experimental studies have linked dysregulation of the glutamatergic system to depression. Glutamate neurotransmission is mediated by ionotropic and metabotropic glutamate receptors, and ionotropic AMPA and NMDA receptors have received extensive attention.
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