Periaqueductal Gray Glutamatergic Transmission Governs Chronic Stress-Induced Depression

Neuropsychopharmacology. 2018 Jan;43(2):302-312. doi: 10.1038/npp.2017.199. Epub 2017 Aug 30.


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.

MeSH terms

  • Anhedonia / physiology
  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Depression / chemically induced
  • Depression / etiology
  • Depression / metabolism*
  • Depression / physiopathology*
  • Disease Models, Animal
  • Glutamic Acid / metabolism*
  • Male
  • Patch-Clamp Techniques
  • Periaqueductal Gray / drug effects
  • Periaqueductal Gray / metabolism*
  • Periaqueductal Gray / physiopathology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism*
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Stress, Psychological / complications
  • Stress, Psychological / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • gamma-Aminobutyric Acid / metabolism*


  • Receptors, AMPA
  • Receptors, Glucocorticoid
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • glutamate receptor ionotropic, AMPA 1