Chronic stress can be a precipitating factor in the onset of depression. Lentiviral-mediated knockdown of HCN1 protein expression and reduction of functional I_h 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_h-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_h was increased in dorsal CA1 neurons following CUS. Furthermore, when dorsal CA1 I_h 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_h, similar to that observed following CUS. Our results suggest that CUS, but not acute stress, leads to an increase in perisomatic I_h in dorsal CA1 neurons and that HCN channels represent a potential target for the treatment of major depressive disorder.

中文翻译：

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h 通道的 Perisomatic 变化调节慢性不可预测压力后的抑郁行为。

慢性压力可能是抑郁症发作的诱发因素。慢病毒介导的 HCN1 蛋白表达的敲低和功能性 I _{h 的}减少产生抗抑郁行为。然而，在抑郁症动物模型中 h 通道是否发生改变尚不清楚。我们发现，在慢性不可预测压力 (CUS)（一种广泛接受的重度抑郁症模型）后，体周 HCN1 蛋白表达和 I _h敏感生理测量值在背侧显着增加，但在腹侧 CA1 区域/神经元中没有显着增加。细胞贴附膜片钳记录证实CUS 后背侧 CA1 神经元中的 perisomatic I _h增加。此外，当背侧 CA1 I _hshRNA-HCN1 减少了 CUS 诱导的行为缺陷。最后，在背侧 CA1 区域注入毒胡萝卜素（一种 SERCA 泵的不可逆抑制剂）的大鼠表现出类似焦虑的行为并增加 I _h，类似于在 CUS 后观察到的情况。我们的结果表明，CUS（而非急性应激）会导致背侧 CA1 神经元中的 perisomatic I _h增加，并且 HCN 通道代表了治疗重度抑郁症的潜在目标。