Increased vulnerability to depressive-like behavior of mice with decreased expression of VGLUT1.
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.
Garcia-Garcia
Alvaro L
AL
Department of Pharmacology, University of Navarra, Pamplona 31080, Spain.
Elizalde
Natalia
N
Matrov
Denis
D
Harro
Jaanus
J
Wojcik
Sonja M
SM
Venzala
Elisabet
E
Ramírez
Maria J
MJ
Del Rio
Joaquin
J
Tordera
Rosa M
RM
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
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