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
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Article info
Publication history
Published online: May 04, 2009
Accepted:
February 19,
2009
Received in revised form:
February 11,
2009
Received:
November 25,
2008
Identification
Copyright
© 2009 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
