Original Article

Periaqueductal Gray Glutamatergic Transmission Governs Chronic Stress-Induced Depression

  • Neuropsychopharmacology volume 43, pages 302312 (2018)
  • doi:10.1038/npp.2017.199
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Abstract

The mechanisms underlying chronic stress-induced dysfunction of glutamatergic transmission that contribute to helplessness-associated depressive disorder are unknown. We investigated the relationship of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and stress, and the neuroplastic changes of stress-induced depression-like behavior in the ventrolateral periaqueductal gray (vlPAG). We conducted whole-cell patch-clamp electrophysiological recordings in the vlPAG neurons. Depression-like behavior was assayed using tail suspension test and sucrose preference test. Surface and cytosolic glutamate receptor 1 (GluR1) AMPA receptor expression was analyzed using western blotting. Phosphorylated GluR1 expression was quantified using western blotting and immunohistochemical analysis. Unpredictable inescapable foot shock stress caused reduction in glutamatergic transmission originating from both presynaptic and postsynaptic loci in the vlPAG that was associated with behavioral despair and anhedonia in chronic stress-induced depression. Pharmacological inhibition of GluR1 function in the vlPAG caused depression-like behavior. Diminished glutamatergic transmission was due to reduced glutamate release presynaptically and enhanced GluR1-endocytosis from the cell surface postsynaptically. Chronic stress-induced neuroplastic changes and maladaptive behavior were reversed and mimicked by administration of glucocorticoid receptor (GR) antagonist and agonist, respectively. However, chronic stress did not affect γ-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission in the vlPAG. These results demonstrate that depression-like behavior is associated with remarkable reduction in glutamatergic, but not GABAergic, transmission in the vlPAG. These neuroplastic changes and maladaptive behavior are attributed to GR-dependent mechanisms. As reduced GluR1-associated responses in the vlPAG contribute to chronic stress-induced neuroplastic changes, this cellular mechanism may be a critical component in the pathogenesis of stress-associated neuropsychiatric disorders.

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Acknowledgements

This work was supported by the Ministry of Science and Technology, Taipei, Taiwan: MOST 105-2628-B-715-003-MY3, 104-2320-B-715-004-MY3, NSC 102-2628-B-715-001, 101-2320-B-715-001-MY3, and MOST 105-2320-B-715-003-MY2 to H-YP and Y-CH; by the Mackay Memorial Hospital MMH-MM-10206, MMH-MM-10302, MMH-MM-10403, and MMH-MM-10503 to H-YP; as well as by the Department of Medicine, Mackay Medical College 1001A03, 1001B07, 1011B02, 1021B08, 1031A01, 1031B07, 104B06, 1042A08, 1051B03, and 1051B04 to H-YP and Y-CH.

Author information

Affiliations

  1. Department of Medicine, Mackay Medical College, New Taipei, Taiwan

    • Yu-Cheng Ho
    • , Ming-Chun Hsieh
    • , Cheng-Yuan Lai
    • , Dylan Chou
    • , Yat-Pang Chau
    •  & Hsien-Yu Peng
  2. Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    • Tzer-Bin Lin
    •  & Dylan Chou
  3. Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan

    • Ming-Chun Hsieh
  4. Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan

    • Cheng-Yuan Lai
  5. Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Chung-Shan Medical University, Taichung, Taiwan

    • Gin-Den Chen

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Corresponding author

Correspondence to Hsien-Yu Peng.

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Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)