Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder.
Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder.
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DOI：
10.1176/appi.ajp.2012.12020248
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Sibille E
中科院分区：
文献类型：
--
作者：
Tripp A;Oh H;Guilloux JP;Martinowich K;Lewis DA;Sibille E
亚属前扣带皮层与重度抑郁症的病理和治疗反应有关。脑源性神经营养因子（BDNF）和GABA功能标记物（包括杏仁核）的低水平在重度抑郁症中有报道，但它们对亚属前扣带皮层功能障碍的影响尚不清楚。使用聚合酶链反应，我们首先评估了BDNF在BDNF功能降低小鼠（BDNF杂合[BDNF +/−]小鼠和BDNF外显子iv敲除[BDNF KIV]小鼠）扣带回皮层中与GABA和神经肽功能相关的15个基因的mRNA表达（定义为BDNF依赖性）的控制程度。然后对51名死后患有重度抑郁症的受试者和对照组（总受试者N=102，其中49%为女性）的亚属前扣带皮层中的基因表达进行量化，并与之前的杏仁核结果进行比较。根据Bdnf +/ -和Bdnf KIV小鼠的结果，基因被分为高、中、无Bdnf依赖组。在死后患有重度抑郁症的人类受试者中，BDNF受体（TRKB）表达减少，但BDNF没有减少。死后抑郁受试者表现出BDNF高度和中度依赖基因的下调，包括树突靶向中间神经元（SST， NPY和CORT）和GABA合成酶（GAD2）的标记。变化扩展到bdnf独立基因（PVALB和GAD1）。男性的变化更大（可能是因为女性的基线表达较低），与先前的杏仁核结果有显著差异，并且不能用性别以外的人口统计学或临床因素来解释。这些平行的人/小鼠分析提供了直接（低TRKB）和间接（BDNF依赖基因的低表达）证据，支持重度抑郁症患者亚属前扣带皮层BDNF信号传导减少，暗示树突靶向GABA神经元和GABA合成，并共同表明重度抑郁症中BDNF /GABA相关病理具有性别和脑区域特异性特征。
The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cortex dysfunction is not known. Using polymerase chain reaction, we first assessed the degree to which BDNF controls mRNA expression (defined as BDNF dependency) of 15 genes relating to GABA and neuropeptide functions in the cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous [Bdnf +/−] mice and BDNF exon-IV knockout [Bdnf KIV] mice). Gene expression was then quantified in the subgenual anterior cingulate cortex of 51 postmortem subjects with major depressive disorder and comparison subjects (total subjects, N=102; 49% were women) and compared with previous amygdala results. Based on the results in Bdnf +/− and Bdnf KIV mice, genes were sorted into high, intermediate, and no BDNF dependency sets. In postmortem human subjects with major depression, BDNF receptor (TRKB) expression, but not BDNF, was reduced. Postmortem depressed subjects exhibited down-regulation in genes with high and intermediate BDNF dependency, including markers of dendritic targeting interneurons (SST, NPY, and CORT) and a GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB and GAD1). Changes were greater in men (potentially because of low baseline expression in women), displayed notable differences from prior amygdala results, and were not explained by demographic or clinical factors other than sex. These parallel human/ mouse analyses provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in the subgenual anterior cingulate cortex in individuals with major depressive disorder, implicate dendritic targeting GABA neurons and GABA synthesis, and, together, suggest a common BDNF-/GABA-related pathology in major depression with sex- and brain region-specific features.
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