|Citation||Garcia-Garcia AL, 2009 PubMed
|Full Info||Garcia-Garcia AL, Elizalde N, Matrov D, Harro J, Wojcik SM, Venzala E et al. Increased vulnerability to depressive-like behavior of mice with decreased expression of VGLUT1. Biol Psychiatry 2009; 66(3): 275-282.
|Hypothesis or 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.
|Method Detail||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.
|Method Keywords||protein analysis; sucrose consumption test; locomotor activity test; forced swimming test; elevated plus maze; Marble Burying Test; novel object recognition test
|Result||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.
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