Increased vulnerability to depressive-like behaviour of mice with decreased expression of VGLUT1

Abstract

Background: Many studies have linked depression to an increase in the excitatory-inhibitory ratio in the forebrain. Presynaptic alterations in a shared pathway of the glutamate/GABA cycle may account for this imbalance. Recent evidence suggests that decreased vesicular glutamate transporter 1 (VGLUT1) levels in the forebrain affects the glutamate/GABA cycle and induces helpless behaviour. Here we studied decreased VGLUT1 as a potencial 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 vesicular glutamate transporter 1 (VGLUT1+/-) and WT. Subsequently, the regulation of neurotransmitter levels, proteins involved in the glutamate/GABA cycle and behaviour by both genotype and chronic mild stress (CMS) was studied. Finally, the effect of chronic imipramine on VGLUT1 control and CMS mice was also studied. Results: VGLUT1+/- mice showed increased neuronal synthesis of glutamate, decreased cortical and hippocampal GABA, VGLUT1 and EAAT1, as well as helplessness and anhedonia. CMS induced an increase of glutamate and a decrease of GABA, VGAT and GAD65 in both areas and led to upregulation 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.