Center for Learning and Memory and Department of Neuroscience, University of Texas at Austin, Austin, TX, USA.
Mol Psychiatry. 2018 Apr;23(4):892-903. doi: 10.1038/mp.2017.28. Epub 2017 Apr 18.
Chronic stress can be a precipitating factor in the onset of depression. Lentiviral-mediated knockdown of HCN1 protein expression and reduction of functional I produce antidepressant behavior. However, whether h-channels are altered in an animal model of depression is not known. We found that perisomatic HCN1 protein expression and I-sensitive physiological measurements were significantly increased in dorsal but not in ventral CA1 region/neurons following chronic unpredictable stress (CUS), a widely accepted model for major depressive disorder. Cell-attached patch clamp recordings confirmed that perisomatic I was increased in dorsal CA1 neurons following CUS. Furthermore, when dorsal CA1 I was reduced by shRNA-HCN1, the CUS-induced behavioral deficits were prevented. Finally, rats infused in the dorsal CA1 region with thapsigargin, an irreversible inhibitor of the SERCA pump, exhibited anxiogenic-like behaviors and increased I, similar to that observed following CUS. Our results suggest that CUS, but not acute stress, leads to an increase in perisomatic I in dorsal CA1 neurons and that HCN channels represent a potential target for the treatment of major depressive disorder.
慢性应激可能是抑郁症发作的一个促成因素。慢病毒介导的 HCN1 蛋白表达敲低和功能性 I 的减少产生抗抑郁行为。然而，在抑郁症动物模型中是否改变了 h 通道尚不清楚。我们发现，慢性不可预测应激（CUS）后，背侧 CA1 区/神经元的胞体 HCN1 蛋白表达和 I 敏感的生理测量显著增加，CUS 是一种广泛接受的重度抑郁症模型。细胞贴附式膜片钳记录证实，CUS 后背侧 CA1 神经元的胞体 I 增加。此外，当通过 shRNA-HCN1 减少背侧 CA1 的 I 时，CUS 引起的行为缺陷得到预防。最后，在背侧 CA1 区域用 thapsigargin（SERCA 泵的不可逆抑制剂）灌注的大鼠表现出焦虑样行为和 I 的增加，类似于 CUS 后观察到的情况。我们的研究结果表明，CUS 而不是急性应激导致背侧 CA1 神经元胞体 I 的增加，HCN 通道代表治疗重度抑郁症的潜在靶点。
