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Abstract：
Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5/6) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients\' response to antidepressant treatment.
摘要：
重度抑郁症（MDD）是一种复杂而毁灭性的疾病，影响所有年龄段的人。尽管在目前的医疗实践中大量使用抗抑郁药，它们的作用机制和MDD的病因尚未完全了解.实验证据支持小白蛋白阳性GABA能神经元（PV-神经元）参与MDD的发病机理。DLX5和DLX6(DLX5/6)编码两种参与皮质GABA能分化和功能的同源结构域转录因子。在老鼠身上，这些基因的表达水平与PV神经元的皮质密度和焦虑样行为相关。相同的基因组区域生成lncRNADLX6-AS1，在人类中,参与精神分裂症和ASD的GABA能调节模块下调。这里,我们表明，Dlx5/6在成年小鼠大脑中的表达水平与强迫游泳试验中的不动时间相关，用来衡量类似抑郁的行为。我们显示抗抑郁药氟西汀（Flx）对正常小鼠的给药诱导，在24小时内，通过TrkB-CREB通路的激活,在大脑皮层中Dlx5、Dlx6和Dlx6-AS1表达的快速和稳定的降低。实验性Dlx5过表达抵消了由Flx治疗诱导的抗抑郁作用。我们的发现表明，Flx给药的短期作用之一是减少GABA能神经元中的Dlx5/6表达，which,反过来,对PV表达和行为特征有直接影响。DLX5/6调节网络中的变异可能与抑郁症的易感性和患者对抗抑郁治疗反应的变异性有关。
