Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.
Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.
复制标题
抑郁症受试者验尸后海马中突触和谷氨酸相关基因的表达改变。
DOI：
10.1017/s1461145712000016
复制
发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Duman RS
中科院分区：
文献类型：
--
作者：
Duric V;Banasr M;Stockmeier CA;Simen AA;Newton SS;Overholser JC;Jurjus GJ;Dieter L;Duman RS
重度抑郁症（MDD）与海马体功能和活动的变化有关，海马体是参与情绪和情绪调节的中央边缘系统区域之一。海马可塑性对应激反应的确切细胞和分子机制尚未完全确定。在这项研究中，我们研究了遗传档案的显微解剖子领域的死后海马诊断为抑郁症和对照组匹配的性别，种族和年龄的主题。通过48 K人HEEBO全基因组微阵列评估齿状回和CA 1的基因表达谱，并通过实时聚合酶链反应（qPCR）确认鉴定的基因的亚组。通路分析揭示了几个基因家族的表达改变，包括参与神经元过程重排的细胞骨架蛋白。基于这一点和证据的海马神经元萎缩的MDD，我们集中在细胞骨架，突触和谷氨酸受体基因的表达。我们的研究结果表明，突触功能/结构相关基因SNAP 25，DLG 2（SAP 93）和MAP 1A，以及2-氨基-3-（5-甲基-3-氧代-1，2-恶唑-4-基）丙酸受体亚基基因GLUR 1和GLUR 3的显著失调。这些人类靶基因中的几个在慢性不可预测压力的大鼠模型中同样失调，并且抗抑郁药治疗逆转了这种影响。总之，这些研究提供了新的证据表明，突触和突触能信号通路的破坏有助于MDD的病理生理学基础，并提供了新的治疗干预的有趣的目标。
Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.