Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Mar 2;82:177-186. doi: 10.1016/j.pnpbp.2017.11.017. Epub 2017 Nov 22.
Major Depressive Disorder (MDD) is a common psychiatric disorder for which available medications are often not effective. The high prevalence of MDD and modest response to existing therapies compels efforts to better understand and treat the disorder. Decreased hippocampal volume with increasing duration of depression suggests altered gene expression or even a decrease in neurogenesis. Tissue punches from the dentate gyrus were collected postmortem from 23 subjects with MDD and 23 psychiatrically-normal control subjects. Total RNA was isolated and whole transcriptome paired-end RNA-sequencing was performed using an Illumina NextSeq 500. For each sample, raw RNA-seq reads were aligned to the Ensembl GRCh38 human reference genome. Analysis revealed 30 genes differentially expressed in MDD compared to controls (FDR<0.05). Down-regulated genes included several with inflammatory function (ISG15, IFI44L, IFI6, NR4A1/Nur-77) and GABBR1 while up-regulated genes included several with cytokine function (CCL2/MCP-1), inhibitors of angiogenesis (ADM, ADAMTS9), and the KANSL1 gene, a histone acetyltransferase. Similar analyses of specific subsets of MDD subjects (suicide vs. non-suicide, single vs. multiple episodes) yielded similar, though not identical, results. Enrichment analysis identified an over-representation of inflammatory and neurogenesis-related (ERK/MAPK) signaling pathways significantly altered in the hippocampal dentate gyrus in MDD. Together, these data implicate neuro-inflammation as playing a crucial role in MDD. These findings support continued efforts to identify adjunctive approaches towards the treatment of MDD with drugs including anti-inflammatory and neuroprotective properties.
重度抑郁症（MDD）是一种常见的精神疾病，现有的药物治疗往往效果不佳。MDD 的高患病率和对现有治疗方法的适度反应促使人们努力更好地理解和治疗这种疾病。随着抑郁持续时间的增加，海马体体积减小，提示基因表达改变，甚至神经发生减少。从 23 名 MDD 患者和 23 名精神病学正常对照者的齿状回中采集组织活检样本。从每个样本中提取总 RNA，使用 Illumina NextSeq 500 进行全转录组配对末端 RNA-seq 分析。对于每个样本，原始 RNA-seq 读数与 Ensembl GRCh38 人类参考基因组进行比对。分析显示，与对照组相比，MDD 中有 30 个基因表达差异（FDR<0.05）。下调的基因包括具有炎症功能的几个基因（ISG15、IFI44L、IFI6、NR4A1/Nur-77）和 GABBR1，而上调的基因包括几个具有细胞因子功能的基因（CCL2/MCP-1）、血管生成抑制剂（ADM、ADAMTS9）和 KANSL1 基因，一种组蛋白乙酰转移酶。对 MDD 特定亚组（自杀与非自杀、单次与多次发作）进行类似的分析，得到了相似但不完全相同的结果。富集分析发现，在 MDD 的海马齿状回中，炎症和神经发生相关（ERK/MAPK）信号通路的过度表达显著改变。总的来说，这些数据表明神经炎症在 MDD 中起着关键作用。这些发现支持继续努力寻找具有抗炎和神经保护特性的药物来辅助治疗 MDD。
