Loss of system xc- induces antidepressant- and anxiolytic-like effects in mice

Today, stress is a major causative factor for a variety of psychiatric disorders. Depression 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, 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 important depression-related brain areas.

In this study we investigated the effect of loss of 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 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 system xc- in the stress response, since the involvement of the antiporter in regulating the response to acute versus chronic stress seems to differ.