Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment.
Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment.
复制标题
DOI：
10.1038/mp.2016.160
复制
发表时间：
2017-06
影响因子：
11
通讯作者：
Kessler JA
中科院分区：
文献类型：
--
作者：
Brooker SM;Gobeske KT;Chen J;Peng CY;Kessler JA
许多抗抑郁药刺激成年海马神经发生，但它们增加神经发生和调节行为的机制尚不完全清楚。在这里，我们表明，海马骨形态发生蛋白（BMP）信号调制抗抑郁药治疗，BMP信号的变化介导抗抑郁药治疗对神经祖细胞增殖和行为的影响。用选择性5-羟色胺再摄取抑制剂氟西汀治疗通过降低BMP 4配体水平和增加BMP抑制剂头蛋白的产生来抑制成年小鼠海马中的BMP信号传导。通过BMP4的病毒过表达增加海马中的BMP信号传导阻断了氟西汀对齿状回增殖和抑郁行为的影响。相反，通过病毒过度表达海马中的noggin或将noggin注入脑室来抑制BMP信号传导，产生抗抑郁和抗焦虑活性，沿着海马神经发生的增加。类似地，在Ascl1表达细胞中II型BMP受体的条件性遗传缺失促进了神经发生并减少了焦虑和抑郁样行为，这表明神经祖细胞有助于BMP信号传导对情感行为的影响。这些观察结果表明，海马体中的BMP信号调节抑郁行为，并且降低BMP信号可能是某些抗抑郁药的作用所必需的。因此，BMP信号转导是治疗抑郁症的一个新的和强大的潜在靶点。
Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin. Increasing BMP signaling in the hippocampus via viral overexpression of BMP4 blocked the effects of fluoxetine on proliferation in the dentate gyrus and on depressive behavior. Conversely, inhibiting BMP signaling via viral overexpression of noggin in the hippocampus or infusion of noggin into the ventricles exerted antidepressant and anxiolytic activity along with an increase in hippocampal neurogenesis. Similarly, conditional genetic deletion of the type II BMP receptor in Ascl1-expressing cells promoted neurogenesis and reduced anxiety- and depression-like behaviors, suggesting that neural progenitor cells contribute to the effects of BMP signaling on affective behavior. These observations indicate that BMP signaling in the hippocampus regulates depressive behavior, and that decreasing BMP signaling may be required for the effects of some antidepressants. Thus BMP signaling is a new and powerful potential target for the treatment of depression.