Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression.
Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression.
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DOI：
10.1017/s1461145709990587
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发表时间：
2010-05
期刊：
影响因子：
--
通讯作者：
Rajkowska G
中科院分区：
文献类型：
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作者：
Karolewicz B;Maciag D;O'Dwyer G;Stockmeier CA;Feyissa AM;Rajkowska G
越来越多的证据表明，在重度抑郁症（MDD）中γ - 氨基丁酸（GABA）系统功能失调。神经影像学研究一致报告抑郁症患者的皮质GABA减少。我们的尸检分析表明，在MDD患者的背外侧前额叶皮质（PFC）中，GABA能中间神经元的密度和大小降低。本研究的目的是检验在MDD患者的同一皮质区域，谷氨酸脱羧酶（GAD，一种GABA合成酶）的水平是否也会降低。通过蛋白质印迹法对13例未用药的MDD患者和13例精神健康对照者的背外侧PFC（BA9）样本中的GAD - 65和GAD - 67蛋白水平进行了研究。与匹配的对照组相比，抑郁症患者的GAD - 67总量显著降低（-34%）。由于近期的神经影像学研究表明抗抑郁药可调节GABA水平，因此进行了额外的实验，以检测8例接受抗抑郁药物治疗的抑郁症患者的GAD水平。与各自的对照组（n = 8）相比，这些抑郁症患者的GAD - 67水平没有变化。无论是否使用抗抑郁药物，抑郁症患者的GAD - 65总量与匹配的对照组相似。GAD - 67水平降低，它定位于GABA神经元的胞体，这进一步支持了我们关于抑郁症患者PFC中GABA能神经元密度降低的观察结果。GAD - 67的降低可能是神经影像学研究中发现的GABA水平降低的原因。此外，我们的数据支持先前的神经影像学观察结果，即抗抑郁药物可使抑郁症患者的GABA缺陷恢复正常。
Accumulating evidence suggests dysfunction of the gamma-aminobutyric acid (GABA) system in major depressive disorder (MDD). Neuroimaging studies consistently report reductions of cortical GABA in depressed patients. Our post-mortem analyses demonstrate a reduction in the density and size of GABAergic interneurons in the dorsolateral prefrontal cortex (PFC) in MDD. The goal of this study was to test whether the level of glutamic acid decarboxylase (GAD), the GABA synthesizing enzyme, will also be reduced in the same cortical region in MDD. Levels of GAD-65 and GAD-67 proteins were investigated by Western blotting in samples from the dorsolateral PFC (BA9) in 13 medication-free subjects with MDD, and 13 psychiatrically healthy controls. The overall amount of GAD-67 was significantly reduced (−34 %) in depressed subjects as compared to matched controls. Since recent neuroimaging studies demonstrate that antidepressants modulate GABA levels, additional experiments were performed to examine the levels of GAD in 8 depressed subjects treated with antidepressant medications. Levels of GAD-67 were unchanged in these depressed subjects as compared to their respective controls (n=8). The overall amounts of GAD-65 were similar in depressed subjects compared to matched controls, regardless of antidepressant medication. Reduced levels of GAD-67, which is localized to somata of GABA neurons, further support our observation of a decreased density of GABAergic neurons in the PFC in depression. It is likely that a decrease in GAD-67 accounts for the reduction in GABA levels revealed by neuroimaging studies. Moreover, our data support previous neuroimaging observations that antidepressant medication normalizes GABA deficits in depression.