Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1

Garcia-Garcia, Alvaro L.; Elizalde, Natalia; Matrov, Denis; Harro, Jaanus; Wojcik, Sonja M.; Venzala, Elisabet; Ramírez, Maria J.; Del Rio, Joaquin; Tordera, Rosa M.

doi:10.1016/j.biopsych.2009.02.027

« Previous Next »Biological Psychiatry
Volume 66, Issue 3 , Pages 275-282, 1 August 2009

Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1

Alvaro L. Garcia-Garcia
- Department of Pharmacology, University of Navarra, Pamplona, Spain
Natalia Elizalde
- Department of Pharmacology, University of Navarra, Pamplona, Spain
Denis Matrov
- Department of Psychology, Estonian Centre of Behavioural and Health Sciences, University of Tartu, Tartu, Estonia
Jaanus Harro
- Department of Psychology, Estonian Centre of Behavioural and Health Sciences, University of Tartu, Tartu, Estonia
Sonja M. Wojcik
- Abteilung Molekulare Neurobiologie, Max-Planck-Institut für Experimentelle Medizin, Göttingen, Germany
Elisabet Venzala
- Department of Pharmacology, University of Navarra, Pamplona, Spain
Maria J. Ramírez
- Department of Pharmacology, University of Navarra, Pamplona, Spain
Joaquin Del Rio
- Department of Pharmacology, University of Navarra, Pamplona, Spain
- Centro investigacíon biomedíca en Red para enfermedades neurodegenerativas (CIBERNED), Spain
Rosa M. Tordera
- Department of Pharmacology, University of Navarra, Pamplona, Spain
- Address reprint requests to Rosa Tordera, Ph.D., Department of Pharmacology, University of Navarra, 31080 Pamplona, Spain

Received 25 November 2008; received in revised form 11 February 2009; accepted 19 February 2009. published online 04 May 2009.

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.

Key Words: Chronic mild stress, GABA, glutamate, major depression, vesicular glutamate transporters, VGLUT2