The cystine/glutamate antiporter as a potential novel target to modulate the stress response?

Introduction: 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.

Methods: 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 in a validated animal model. 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.

Results and discussion: Interestingly we found decreased depressive- and anxiety- like behavior in the naïve xCT-/- mice in all of the tests conducted. Unexpectedly however the decrease in depressive- and anxiety- like behavior faded and disappeared after vehicle and corticosterone treatment. 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.

Research support: This research was supported by the Fund for Scientific Research Flanders (FWO, grant G.038412N), the Queen Elisabeth Medical Foundation (G.S.K.E.), and the Vrije Universiteit Brussel (Strategic Research Program, grant SRP40).