Sex differences in glutamate receptor gene expression in major depression and suicide
Sex differences in glutamate receptor gene expression in major depression and suicide
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DOI：
10.1038/mp.2015.91
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发表时间：
2015-09-01
影响因子：
11
通讯作者：
Sodhi, M. S.
中科院分区：
文献类型：
--
作者：
Gray, A. L.;Hyde, T. M.;Sodhi, M. S.
越来越多的数据表明，谷氨酸系统在重度抑郁症（MDD）中被破坏，最近的临床研究表明，氯胺酮，N-甲基-D-天冬氨酸（NMDA）谷氨酸受体（GluR）的拮抗剂，具有快速的抗抑郁疗效。在这里，我们报告的结果，从一个大的队列的尸检对象，包括受试者与MDD和控制的基因表达研究。我们的数据显示，MDD患者背外侧前额叶皮层（DLPFC）中检测的大多数多巴胺能基因的表达水平较高（F-21，F-59 = 2.32，P = 0.006）。事后数据表明，这些基因表达差异主要发生在女性受试者中。GRIN 1、GRIN 2A-D、GRIA 2 -4、GRIK 1 -2、GRM 1、GRM 4、GRM 5和GRM 7在女性MDD患者中的表达水平较高。相反，GRM 5表达在男性MDD患者中相对于男性对照较低。当MDD自杀者与MDD非自杀者进行比较时，自杀者中GRIN 2B、GRIK 3和GRM 2的表达水平较高。检测到几个额外的基因的较高表达水平，但这些在多重比较校正后没有统计学显著性。总之，我们的分析表明，抑郁症女性DLPFC中GluR的调节普遍中断，自杀者和男性组中有更特异性的GluR改变。这些数据揭示了进一步的证据，除了NMDA受体，AMPA，红藻氨酸和代谢型GluRs可能是快速作用的抗抑郁药物的发展目标。
Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F-21,F-59 = 2.32, P = 0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.