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.
Chemical Biology Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology, Hyderabad, India.
Biol Psychiatry. 2014 Aug 1;76(3):231-8. doi: 10.1016/j.biopsych.2013.09.024. Epub 2013 Oct 3.
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.
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.
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.
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.
抑郁症是一种复杂的神经精神综合征，通常非常严重且危及生命。尽管在理解神经生物学方面取得了显著进展，但抑郁症的病因仍然难以捉摸。在这项研究中，我们研究了慢性挫败应激诱导的出现类似抑郁表型的小鼠前额叶皮层中的分子机制。
通过对 C57BL/6 小鼠进行为期 10 天的社交挫败范式，诱导出现类似抑郁的表型。通过（1）H-[(13)C]-磁共振波谱测量前额叶皮层兴奋性（谷氨酸能）和抑制性（γ-氨基丁酸 [GABA]能）神经元的代谢活性，同时输注[1,6-(13)C2]葡萄糖。此外，通过定量聚合酶链反应监测与谷氨酸能和 GABA 能途径相关的基因的表达水平。
出现类似抑郁表型的小鼠在前额叶皮层中显示出谷氨酸、谷氨酰胺、N-乙酰天冬氨酸和牛磺酸水平显著降低。最重要的是，从[1,6-(13)C2]葡萄糖获得的谷氨酸-C4、谷氨酸-C3 和 GABA-C2 的（13）C 标记减少表明抑郁小鼠中的谷氨酸能和 GABA 能神经元代谢和神经递质循环减少。减少的谷氨酰胺-C4 标记表明抑郁时神经递质循环减少。定量聚合酶链反应分析显示，编码 GABA 合成和谷氨酸从突触清除的酶的 Gad1 和 Eaat2 基因的转录物减少。
这些数据表明，出现类似抑郁表型的小鼠中谷氨酸能和 GABA 能神经元的活性降低，这得到了涉及谷氨酸和 GABA 途径的基因表达的分子数据的支持。
