title: Increased vulnerability to depressive-like behavior of mice with decreased expression of VGLUT1.
abstract: BACKGROUND
  Many studies link depression to an increase in the excitatory-inhibitory ratio in the forebrain. Presynaptic alterations in a shared pathway of the glutamate/gamma-aminobutyric acid (GABA) cycle may account for this imbalance. Evidence suggests that decreased vesicular glutamate transporter 1 (VGLUT1) levels in the forebrain affect the glutamate/GABA cycle and induce helpless behavior. We studied decreased VGLUT1 as a potential factor enhancing a depressive-like phenotype in an animal model.
  
  
  METHODS
  Glutamate and GABA synthesis as well as oxidative metabolism were studied in heterozygous mice for the VGLUT1+/- and wildtype. The regulation of neurotransmitter levels, proteins involved in the glutamate/GABA cycle, and behavior by both genotype and chronic mild stress (CMS) were studied. Finally, the effect of chronic imipramine on VGLUT1 control and CMS mice was studied.
  
  
  RESULTS
  VGLUT1+/- mice showed increased neuronal synthesis of glutamate; decreased cortical and hippocampal GABA, VGLUT1, and excitatory amino acid transporter 1 (EAAT1) as well as helplessness and anhedonia. CMS induced an increase of glutamate and a decrease of GABA, the vesicular GABA transporter (VGAT), and glutamic acid decarboxylase 65 (GAD65) in both areas and led to upregulation of EAAT1 in the hippocampus. Moreover, CMS induced anhedonia, helplessness, anxiety, and impaired recognition memory. VGLUT1+/- CMS mice showed a combined phenotype (genotype plus stress) and specific alterations, such as an upregulation of VGLUT2 and hyperlocomotion. Moreover, an increased vulnerability to anhedonia and helplessness reversible by chronic imipramine was shown.
  
  
  CONCLUSIONS
  These studies highlight a crucial role for decreased VGLUT1 in the forebrain as a biological mediator of increased vulnerability to chronic mild stress.
authors.affiliation: Department of Pharmacology, University of Navarra, Pamplona 31080, Spain.
authors.forename: Alvaro L
authors.initials: AL
authors.lastname: Garcia-Garcia
authors.forename: Natalia
authors.initials: N
authors.lastname: Elizalde
authors.forename: Denis
authors.initials: D
authors.lastname: Matrov
authors.forename: Jaanus
authors.initials: J
authors.lastname: Harro
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Wojcik
authors.forename: Elisabet
authors.initials: E
authors.lastname: Venzala
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramírez
authors.forename: Joaquin
authors.initials: J
authors.lastname: Del Rio
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Tordera
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics; D002247:Carbon Isotopes / Q000378:metabolism; D003863:Depression / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology*; D003576:Electron Transport Complex IV / Q000378:metabolism; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009483:Neuropsychological Tests; D021641:Recognition, Psychology / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013550:Swimming; D050598:Vesicular Glutamate Transport Protein 1 / Q000172:deficiency / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid
chemical_list: D002247:Carbon Isotopes; D027341:Excitatory Amino Acid Transporter 1; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D003576:Electron Transport Complex IV; D005968:Glutamate Decarboxylase