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Metabotropic glutamate receptor subtype 3 gates acute stress-induced dysregulation of amygdalo-cortical function

Molecular Psychiatry volume 24, pages 916–927 (2019)Cite this article

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Abstract

Stress can precipitate or worsen symptoms of many psychiatric disorders by dysregulating glutamatergic function within the prefrontal cortex (PFC). Previous studies suggest that antagonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3) reduce stress-induced anhedonia through actions in the PFC, but the mechanisms by which these receptors act are not known. We now report that activation of mGlu3 induces long-term depression (LTD) of excitatory transmission in the PFC at inputs from the basolateral amygdala. Our data suggest mGlu3-LTD is mediated by postsynaptic AMPAR internalization in PFC pyramidal cells, and we observed a profound impairment in mGlu3-LTD following a single, 20-min restraint stress exposure. Finally, blocking mGlu3 activation in vivo prevented the stress-induced maladaptive changes to amydalo-cortical physiology and motivated behavior. These data demonstrate that mGlu3 mediates stress-induced physiological and behavioral impairments and further support the potential for mGlu3 modulation as a treatment for stress-related psychiatric disorders.

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Acknowledgements

The Authors thank Douglas Shaw, Jennifer Zachry, Weimin Peng, and Dr. Zixiu Xiang for their technical assistance and advice. This work was supported by the National Institutes of Health (NIH) grants R01MH062646 and R37NS031373 (P.J.C.). M.E.J. was supported by the NIH grant T32MH093366 and a postdoctoral fellowship through the Pharmaceutical Research and Manufacturers of America Foundation. Behavioral experiments were performed through the Murine Neurobehavior Core lab at the Vanderbilt University Medical Center.

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Authors and Affiliations

  1. Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA

    Max E. Joffe, Craig W. Lindsley & P. Jeffrey Conn

  2. Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN, 37232, USA

    Max E. Joffe, Chiaki I. Santiago, Julie L. Engers, Craig W. Lindsley & P. Jeffrey Conn

  3. Vanderbilt University, Nashville, TN, 37232, USA

    Chiaki I. Santiago

  4. Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA

    Craig W. Lindsley

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Correspondence to P. Jeffrey Conn.

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Conflict of interest

C.W.L. has been funded by the NIH, Johnson and Johnson, Bristol-Myers Squibb, AstraZeneca, Michael J. Fox Foundation, as well as Seaside Therapeutics. He has consulted for AbbVie and received compensation. P.J.C. has been funded by NIH, AstraZeneca, Bristol-Myers Squibb, Michael J. Fox Foundation, Dystonia Medical Research Foundation, CHDI Foundation, and Thome Memorial Foundation. Over the past 3 years he has served on the Scientific Advisory Boards for Michael J. Fox Foundation, Stanley Center for Psychiatric Research Broad Institute, Karuna Pharmaceuticals, Lieber Institute for Brain Development, Clinical Mechanism and Proof of Concept Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder. C.W.L. and P.J.C. are inventors on patents that protect different classes of metabotropic glutamate allosteric modulators. M.E.J., C.I.S., and J.L.E. declare no conflict of interest.

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Joffe, M.E., Santiago, C.I., Engers, J.L. et al. Metabotropic glutamate receptor subtype 3 gates acute stress-induced dysregulation of amygdalo-cortical function. Mol Psychiatry 24, 916–927 (2019). https://doi.org/10.1038/s41380-017-0015-z

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