Wu Li-Min, Han Hui, Wang Qu-Nan, Hou Hai-Long, Tong Hui, Yan Xue-Bo, Zhou Jiang-Ning
Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology and Biophysics, School of Life Science, University of Science and Technology of China, Hefei, China.
Neuropsychopharmacology. 2007 Dec;32(12):2500-10. doi: 10.1038/sj.npp.1301386. Epub 2007 Mar 28.
Clinical investigations present much evidence that the glucocorticoid receptor (GR) antagonist mifepristone leads to a rapid amelioration of depression. The molecular mechanisms of mifepristone involved in the treatment of depression are not fully understood. Depression is associated with hippocampal plasticity, for which increased excitatory amino acid (EAA) release in CA3 induced by chronic stress is responsible, and glucocorticoids have a permissive role and act synergistically with EAAs in producing neuronal damage. Moreover, glucocorticoids increase synapsin I, which has a key role in the release of neurotransmitter, including EAAs. Hereby, we hypothesize that major depression involves synapsin I alteration and that mifepristone blocks this alteration. In the present study, we observed both the expression of hippocampal synapsin I and depression-associated behavior in a rat model of depression induced by chronic unpredictable mild stress (CUMS). The result showed that a region-dependent synapsin I alteration occurs in the rat hippocampus after 21 days of CUMS, that is, it increases in dentate gyrus (DG)/CA3 and decreases in the CA1 region. Correlation analysis indicated that the decrease of synapsin I in CA1 is highly correlated with the increase in the DG/CA3 subfield. Simultaneously, the region-dependent alteration of synapsin I is correlated with depression-associated behaviors. Both the alteration of synapsin I and the depression-associated behavior were rapidly restored after treatment with mifepristone for 1 week. The result suggests that the molecular mechanism underlying the treatment of depression with mifepristone is associated with the rapid repair of the synaptic alteration.
临床研究提供了大量证据表明，糖皮质激素受体（GR）拮抗剂米非司酮可迅速改善抑郁症。米非司酮治疗抑郁症所涉及的分子机制尚未完全明确。抑郁症与海马可塑性有关，慢性应激诱导的CA3区兴奋性氨基酸（EAA）释放增加是其原因，糖皮质激素在其中起允许作用，并与EAA协同作用导致神经元损伤。此外，糖皮质激素可增加突触素I，其在包括EAA在内的神经递质释放中起关键作用。因此，我们推测重度抑郁症涉及突触素I的改变，而米非司酮可阻断这种改变。在本研究中，我们观察了慢性不可预测轻度应激（CUMS）诱导的大鼠抑郁症模型中海马突触素I的表达及与抑郁相关的行为。结果显示，CUMS处理21天后，大鼠海马区出现了区域依赖性的突触素I改变，即齿状回（DG）/CA3区增加而CA1区减少。相关性分析表明，CA1区突触素I的减少与DG/CA3子区域的增加高度相关。同时，突触素I的区域依赖性改变与抑郁相关行为有关。米非司酮治疗1周后，突触素I的改变和抑郁相关行为均迅速恢复。结果表明，米非司酮治疗抑郁症的分子机制与突触改变的快速修复有关。
