Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression.
Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression.
复制标题
在慢性抑郁症的慢性不可预测的压力模型中GABA能标记表达的表征。
DOI：
10.1177/2470547017720459
复制
发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Sanacora G
中科院分区：
文献类型：
--
作者：
Banasr M;Lepack A;Fee C;Duric V;Maldonado-Aviles J;DiLeone R;Sibille E;Duman RS;Sanacora G
越来越多的证据表明，严重抑郁症患者的大脑中GABA能神经递质系统发生了变化。然而，关于这些变化的程度或与这些变化相关的潜在机制的信息很少。由于应激是抑郁症发作的一个公认的诱因，我们试图探索慢性应激对GABA能中间神经元的影响。采用蛋白质印迹分析和实时定量聚合酶链式反应技术，研究了持续5周的慢性不可预测应激暴露对大鼠额叶皮质和海马区GABA合成酶(GAD65和GAD67)、钙结合蛋白(钙结合蛋白、钙结合蛋白和钙结合蛋白)以及GABA能神经元共表达神经肽(生长抑素、神经肽Y、血管活性肠肽和胆囊收缩素)表达的影响。我们还研究了皮质酮和地塞米松对体外培养的大脑皮层和海马区这些标记物的影响。我们发现，慢性不可预测应激导致慢性不可预测应激暴露的大鼠前额叶皮质和海马区GAD67蛋白水平显著降低，但没有检测到GAD65蛋白表达的变化。体外培养的大脑皮层神经元中也发现了类似的蛋白表达变化。此外，我们的结果提供了明确的证据表明，在前额叶皮质中，中间神经元群体(S)的标志物，即生长抑素和神经肽Y，可能是选择性地易受慢性应激的影响。总之，这项工作强调了慢性应激诱导大鼠GABA能中间神经元的局部和细胞类型选择效应。这些发现提供了更多支持证据，表明应激诱导的GABA神经元功能障碍和细胞脆弱性在应激相关疾病的病理生理学中发挥关键作用，包括严重的抑郁障碍。
Evidence continues to build suggesting that the GABAergic neurotransmitter system is altered in brains of patients with major depressive disorder. However, there is little information available related to the extent of these changes or the potential mechanisms associated with these alterations. As stress is a well-established precipitant to depressive episodes, we sought to explore the impact of chronic stress on GABAergic interneurons. Using western blot analyses and quantitative real-time polymerase chain reaction, we assessed the effects of five-weeks of chronic unpredictable stress exposure on the expression of GABA-synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin, parvalbumin, and calretinin), and neuropeptides co-expressed in GABAergic neurons (somatostatin, neuropeptide Y, vasoactive intestinal peptide, and cholecystokinin) in the prefrontal cortex and hippocampus of rats. We also investigated the effects of corticosterone and dexamethasone exposure on these markers in vitro in primary cortical and hippocampal cultures. We found that chronic unpredictable stress induced significant reductions of GAD67 protein levels in both the prefrontal cortex and hippocampus of chronic unpredictable stress-exposed rats but did not detect changes in GAD65 protein expression. Similar protein expression changes were found in vitro in cortical neurons. In addition, our results provide clear evidence of reduced markers of interneuron population(s), namely somatostatin and neuropeptide Y, in the prefrontal cortex, suggesting these cell types may be selectively vulnerable to chronic stress. Together, this work highlights that chronic stress induces regional and cell type-selective effects on GABAergic interneurons in rats. These findings provide additional supporting evidence that stress-induced GABA neuron dysfunction and cell vulnerability play critical roles in the pathophysiology of stress-related illnesses, including major depressive disorder.