Depression and anxiety disorders are some of the most common and important health problems worldwide. The current therapeutic approaches for these psychiatric conditions are often limited in efficacy, and may be associated with serious side effects, such as sedation, memory impairment, or physical dependence. Therefore, novel pharmacological targets with an improved therapeutic profile are currently of urgent need. System xc- is a plasma membrane transporter that imports cystine and exports glutamate in the extracellular space. Although system xc- can act as a source of extrasynaptic glutamate release, the physiologic role played by this transporter in neurotransmission and behavior has been difficult to unravel due to the lack of selective inhibitors. In order to elucidate the role played by system xc- in vivo, we have recently characterized the behavioral changes observed after transgenic loss of xCT (the specific subunit of system xc-) in mice. Interestingly, preliminary data indicate that xCT knock-out mice show an anxiolytic and antidepressant-like phenotype, as evidenced by significant changes in parameters obtained from anxiety-based tests (open-field and light/dark tests), and depression-based test (forced swim test). This shift in behavior occurred in the absence of significant changes in motor behavior, as evidenced by a battery of motor tests, such as the open-field, rotarod, nest building, and adhesive removal tests, and was stable across ageing, indicating the presence of an endophenotype in the xCT knock-out mice. These novel findings extend the previous observations that targeting the glutamatergic system might form the basis of novel therapeutic interventions for mood disorders. Furthermore, they confirm an active participation of nonsynaptic glutamate release, to behavioral traits in physiological conditions. In conclusion, our data strongly suggest that targeting system xc- might represent a novel therapeutic intervention for mood disorders.
Original languageEnglish
Title of host publicationResearch in Psychiatry Day organized by the Belgian College for Neuropsychopharmacology and Biological Psychiatry, 27 September 2013, Leuven
Publication statusPublished - 27 Sep 2013

    Research areas

  • system xc-, depression, anxiety, glutamate

ID: 2357088