期刊
NEUROCHEMISTRY INTERNATIONAL
卷 137, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2020.104750
关键词
GABA; Glutamate; Glutamine; Neuron-Glia interaction; Neurotransmission; C-13 Nuclear magnetic resonance spectroscopy
资金
- Department of Biotechnology Government of India [BT/PR4019/MED/30/675/2011]
- National Institutes of Health [R01 DK108283, R01 AA021984]
Major depressive disorder is the leading cause of disability and suicidality worldwide. Here, we evaluated neural metabolic activity in prefrontal cortex (PFC) in C57BL6 mice undergoing a chronic unpredictable mild stress (CUMS) for three weeks to induce depression. Further, the efficacy of Lanicemine, a low trapping NMDA receptor antagonist, on behavioral and neurometabolic measures in CUMS mice was evaluated. The PFC neuronal and astroglial metabolic activity was evaluated by Proton Observed Carbon Edited (POCE) MR spectroscopy together with an infusion of [1,6-C-13(2)]glucose and [2-C-13]acetate, respectively. The rates of glutamatergic, GABAergic and astrocytic TCA cycles and neurotransmitter cycling were obtained by fitting a three-compartment metabolic model to C-13 turnover of amino acids. Mice subjected to CUMS exhibited significantly reduced sucrose preference (CUMS 58.0 +/- 12.5%, n = 29; Control 86.3 +/- 6.4%, n = 30; p < 0.0001), and increased immobility (CUMS 146.1 +/- 60.8s, n = 29; Control 29.9 +/- 19.3s, n = 30; p < 0.0001) in the forced swim test. The concentrations of C-13 labeled amino acids from [2-C-13]acetate were decreased suggesting reduced astroglial metabolic activity in CUMS mice. The glutamatergic and GABAergic TCA cycle rates were decreased in CUMS mice when compared with controls. In addition, GABA-glutamine and glutamate-glutamine neurotransmitter cycling were reduced in mice subjected to CUMS regimen. Most interestingly, a short time intervention of lanicemine restored behavioral measures (sucrose preference and immobility), and rates of glucose oxidation in glutamatergic and GABAergic neurons in CUMS mice. In summary, our findings suggest that depression leads to a reduction in excitatory and inhibitory neurotransmission in PFC, and targeting glutamatergic pathway may have potential therapeutic role in chronic depression.
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