THE GLUTAMATE HYPOTHESIS OF DEPRESSION: Loss of system xc- induces antidepressant- and anxiolytic- like effects in mice

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Thomas Demuyser, Eduard Bentea, Lauren Deneyer, Giulia Albertini, Joeri Van Liefferinge, Ellen Merckx, Ann Massie, Ilse Smolders
Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium

In modern society, stress is a major causative factor for a variety of psychiatric disorders. Depression, one of the main causes of disability worldwide, is a multimodal disease with chronic stress considered as a 'trigger' for depressive episodes. Depression and comorbid anxiety are usually related to a malfunctioning monoaminergic system, nowadays however compelling evidence points at an important role of glutamate in the etiology of the 'depressed/anxious brain'. Being the major excitatory neurotransmitter in the central nervous system, glutamate can potentially have important excitotoxic effects. System xc- is the cystine/glutamate antiporter and the major source of extrasynaptic glutamate in some important depression-related brain areas, where it can be an interesting new target for improved psychopharmacological treatment.

In this study we investigated the effect of loss of functional system xc- (e.g. deletion of the specific light chain subunit xCT; xCT-/-), on chronic stress induced depression and anxiety. Therefore we subjected xCT-/- and xCT+/+ mice, treated with chronic corticosterone injections (excessive chronic stress), to a battery of acute stress-based tests for depressive- and anxiety- like behavior and compared their behavior to vehicle treated and naïve animals.
Interestingly we found decreased depressive- and anxiety- like behavior in the naïve and vehicle treated xCT-/- mice in most of the tests conducted. Unexpectedly however the decrease in depressive- and anxiety- like behavior was lost in the corticosterone treated xCT-/- mice, in comparison to their xCT+/+ littermates. These findings support further research for the role of system xc- in the stress response, since the involvement of the antiporter in regulating the response to acute versus chronic stress seems to differ.
Original languageEnglish
Title of host publicationResearch in Psychiatry Day BCNBP, Duffel, Belgium 2014
Publication statusPublished - 2014


  • System xc-
  • Corticosterone mouse model
  • Glutamate hypothesis of depression and anxiety

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