title: Absence of system xc- in mice decreases anxiety and depressive-like behavior without affecting sensorimotor function or spatial vision.
abstract: There is considerable preclinical and clinical evidence indicating that abnormal changes in glutamatergic signaling underlie the development of mood disorders. Astrocytic glutamate dysfunction, in particular, has been recently linked with the pathogenesis and treatment of mood disorders, including anxiety and depression. System xc- is a glial cystine/glutamate antiporter that is responsible for nonvesicular glutamate release in various regions of the brain. Although system xc- is involved in glutamate signal transduction, its possible role in mediating anxiety or depressive-like behaviors is currently unknown. In the present study, we phenotyped adult and aged system xc- deficient mice in a battery of tests for anxiety and depressive-like behavior (open field, light/dark test, elevated plus maze, novelty suppressed feeding, forced swim test, tail suspension test). Concomitantly, we evaluated the sensorimotor function of system xc- deficient mice, using motor and sensorimotor based tests (rotarod, adhesive removal test, nest building test). Finally, due to the presence and potential functional relevance of system xc- in the eye, we investigated the visual acuity of system xc- deficient mice (optomotor test). Our results indicate that loss of system xc- does not affect motor or sensorimotor function, in either adult or aged mice, in any of the paradigms investigated. Similarly, loss of system xc- does not affect basic visual acuity, in either adult or aged mice. On the other hand, in the open field and light/dark tests, and forced swim and tail suspension tests respectively, we could observe significant anxiolytic and antidepressive-like effects in system xc- deficient mice that in certain cases (light/dark, forced swim) were age-dependent. These findings indicate that, under physiological conditions, nonvesicular glutamate release via system xc- mediates aspects of higher brain function related to anxiety and depression, but does not influence sensorimotor function or spatial vision. As such, modulation of system xc- might constitute the basis of innovative interventions in mood disorders.
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Eduard
authors.initials: E
authors.lastname: Bentea
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Demuyser
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Joeri
authors.initials: J
authors.lastname: Van Liefferinge
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Giulia
authors.initials: G
authors.lastname: Albertini
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Lauren
authors.initials: L
authors.lastname: Deneyer
authors.affiliation: Laboratory of Neuroplasticity and Neuroproteomics, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Nys
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Merckx
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Technology, Faculty of Medicine, Niigata University, Niigata, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.affiliation: Laboratory of Neuroplasticity and Neuroproteomics, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Arckens
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address: Ilse.Smolders@vub.ac.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics; D000375:Aging; D027182:Amino Acid Transport System y+ / Q000172:deficiency* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000503:physiopathology*; D003863:Depression / Q000235:genetics* / Q000503:physiopathology*; D005106:Exploratory Behavior / Q000502:physiology; D005247:Feeding Behavior; D005838:Genotype; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D011597:Psychomotor Performance; D013028:Space Perception / Q000502:physiology*; D013550:Swimming / Q000523:psychology; D013997:Time Factors; D014792:Visual Acuity / Q000235:genetics
chemical_list: D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse
keywords: Anxiety; Depression; Sensorimotor; System xc-; Vision; xCT