The Role of Dendritic Brain-Derived Neurotrophic Factor Transcripts on Altered Inhibitory Circuitry in Depression
The Role of Dendritic Brain-Derived Neurotrophic Factor Transcripts on Altered Inhibitory Circuitry in Depression
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DOI：
10.1016/j.biopsych.2018.09.026
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发表时间：
2019-03-15
影响因子：
10.6
通讯作者：
Sibille, Etienne
中科院分区：
文献类型：
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作者：
Oh, Hyunjung;Piantadosi, Sean C.;Sibille, Etienne
背景技术背景：脑源性神经营养因子（BDNF）和生长抑素（SST）的平行下调，抑制γ-氨基丁酸中间神经元的目标锥体细胞树突的标志物，已被报道在几个大脑区域的主题与抑郁症（MDD）。啮齿动物遗传学研究表明，它们是相关的，都有助于疾病。然而，它们对疾病病理生理学的作用机制仍然难以捉摸。方法：通过定量聚合酶链反应，我们确定了MDD患者和匹配的对照受试者（n = 19/组）以及暴露于慢性应激或对照条件的C57 BL/6 J小鼠（n = 12/组）前额叶皮质中脑源性神经营养因子转录变体和突触标记物的表达水平。接下来，我们使用短发夹RNA抑制BDNF转录物的长3 '非翻译区（L-3'-UTR），并研究细胞形态，基因表达和behavior.Results的变化：L-3'-UTR含有BDNF信使RNA，迁移到锥体神经元的远端树突，选择性减少，其表达与SST表达在MDD受试者的前额叶皮层高度相关。类似的下调也发生在慢性应激的小鼠身上。我们接下来表明，Bdnf L-3'-UTR敲低足以诱导1）皮质神经元中的树突收缩，2）细胞特异性MDD样基因变化（包括Sst下调），以及3）抑郁和焦虑样行为。翻译的有效性的BDNF L-3'-UTR短发夹RNA处理的小鼠证实了重大跨物种相关性的变化，在MDD相关的基因expression. CONCLUSIONS：这些发现提供了证据的一种新的MDD相关的病理机制，连接本地神经营养支持，锥体细胞结构，树突状抑制，情绪调节。
BACKGROUND: A parallel downregulation of brain-derived neurotrophic factor (BDNF) and somatostatin (SST), a marker of inhibitory gamma-aminobutyric acid interneurons that target pyramidal cell dendrites, has been reported in several brain areas of subjects with major depressive disorder (MDD). Rodent genetic studies suggest that they are linked and that both contribute to the illness. However, the mechanism by which they contribute to the pathophysiology of the illness has remained elusive.METHODS: With quantitative polymerase chain reaction, we determined the expression level of BDNF transcript variants and synaptic markers in the prefrontal cortex of patients with MDD and matched control subjects (n = 19/ group) and of C57BL/6J mice exposed to chronic stress or control conditions (n = 12/group). We next suppressed Bdnf transcripts with long 3' untranslated region (L-3'-UTR) using short hairpin RNA and investigated changes in cell morphology, gene expression, and behavior.RESULTS: L-3'-UTRs containing BDNF messenger RNAs, which migrate to distal dendrites of pyramidal neurons, are selectively reduced, and their expression was highly correlated with SST expression in the prefrontal cortex of subjects with MDD. A similar downregulation occurs in mice submitted to chronic stress. We next show that Bdnf L-3'-UTR knockdown is sufficient to induce 1) dendritic shrinkage in cortical neurons, 2) cell-specific MDD-like gene changes (including Sst downregulation), and 3) depressive- and anxiety-like behaviors. The translational validity of the Bdnf L-3'-UTR short hairpin RNA-treated mice was confirmed by significant cross-species correlation of changes in MDD-associated gene expression.CONCLUSIONS: These findings provide evidence for a novel MDD-related pathological mechanism linking local neurotrophic support, pyramidal cell structure, dendritic inhibition, and mood regulation.