Dysfunctional glutamatergic and γ-aminobutyric acidergic activities in prefrontal cortex of mice in social defeat model of depression.
BACKGROUND
Depression is a complex neuropsychiatric syndrome that is often very severe and life threatening. In spite of the remarkable progress in understanding the neural biology, the etiopathophysiology of depression is still elusive. In this study, we have investigated molecular mechanisms in the prefrontal cortex of mice showing depression-like phenotype induced by chronic defeat stress.


METHODS
Depression-like phenotype was induced in C57BL/6 mice by subjecting them to a 10-day social defeat paradigm. The metabolic activity of excitatory (glutamatergic) and inhibitory (γ-aminobutyric acid [GABA]ergic) neurons of the prefrontal cortex was measured by (1)H-[(13)C]-nuclear magnetic resonance spectroscopy together with infusion of [1,6-(13)C2]glucose. In addition, the expression level of genes associated with glutamatergic and GABAergic pathways was monitored by quantitative polymerase chain reaction.


RESULTS
Mice showing depression-like phenotype exhibit significant reduction in the levels of glutamate, glutamine, N-acetyl aspartate, and taurine in the prefrontal cortex. Most importantly, findings of reduced (13)C labeling of glutamate-C4, glutamate-C3, and GABA-C2 from [1,6-(13)C2]glucose indicate decreased glutamatergic and GABAergic neuronal metabolism and neurotransmitter cycling in the depressed mice. The reduced glutamine-C4 labeling suggests decreased neurotransmitter cycling in depression. Quantitative polymerase chain reaction analysis revealed reduced transcripts of Gad1 and Eaat2 genes, which code for enzymes involved in the synthesis of GABA and the clearance of glutamate from synapses, respectively.


CONCLUSIONS
These data indicate that the activities of glutamatergic and GABAergic neurons are reduced in mice showing a depression-like phenotype, which is supported by molecular data for the expression of genes involved in glutamate and GABA pathways.
Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India.
Pandichelvam
P
Veeraiah
Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India.
Judith Miriam
JM
Noronha
Chemical Biology Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India.
Swati
S
Maitra
Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India.
Puneet
P
Bagga
Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India.
Nitin
N
Khandelwal
Chemical Biology Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India.
Sumana
S
Chakravarty
Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India.
Arvind
A
Kumar
Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India. Electronic address: abpatel@ccmb.res.in.
Anant B
AB
Patel
D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D003863:Depression / Q000378:metabolism; D003866:Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D012919:Social Behavior; D013315:Stress, Psychological / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
Brain; NMR spectroscopy; cerebral metabolism; gene expression; glia; mood disorders