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 [1,6-13C2]glucose and [2-13C]acetate, respectively. The rates of glutamatergic, GABAergic and astrocytic TCA cycles and neurotransmitter cycling were obtained by fitting a three-compartment metabolic model to 13C 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 13C labeled amino acids from [2-13C]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.

中文翻译：

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慢性不可预测的轻度抑郁症抑郁模型中神经元和星形胶质细胞代谢活性受损：Lanicemine可逆转行为和代谢缺陷。

严重的抑郁症是全球残疾和自杀的主要原因。在这里，我们评估了C57BL6小鼠的前额叶皮层（PFC）中的神经代谢活性，这些小鼠经历了慢性不可预测的轻度应激（CUMS），持续了三周以诱发抑郁。此外，评估了Lanicemine（一种低捕获NMDA受体拮抗剂）对CUMS小鼠的行为和神经代谢指标的功效。PFC神经元和星形胶质细胞的代谢活性通过质子观测碳编辑（POCE）MR光谱法和分别注入[1,6-13C2]葡萄糖和[2-13C]乙酸盐进行评估。谷氨酸能，GABA能和星形细胞TCA循环和神经递质循环的比率是通过将三室代谢模型拟合为氨基酸的13 C转换来获得的。接受CUMS的小鼠表现出明显降低的蔗糖偏爱性（CUMS 58.0±12.5％，n = 29;对照86.3±6.4％，n = 30; p <0.0001），并且不动性增加（CUMS 146.1±60.8s，n = 29;对照29.9±19.3s，n = 30； p <0.0001）。来自[2-13C]乙酸盐的13C标记氨基酸的浓度降低，表明CUMS小鼠的星形胶质代谢活性降低。与对照组相比，CUMS小鼠的谷氨酸和GABA能TCA循环速率降低。另外，在接受CUMS方案的小鼠中，GABA-谷氨酰胺和谷氨酸-谷氨酰胺神经递质循环减少。最有趣的是，短时干预Lanicemine可以恢复CUMS小鼠的谷氨酸能和GABA能神经元的行为指标（蔗糖偏爱和固定性）以及葡萄糖氧化速率。