Functional coupling of Tmem74 and HCN1 channels regulates anxiety-like behavior in BLA neurons
Functional coupling of Tmem74 and HCN1 channels regulates anxiety-like behavior in BLA neurons
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Tmem74 和 HCN1 通道的功能耦合调节 BLA 神经元的焦虑样行为
DOI：
10.1038/s41380-019-0402-8
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发表时间：
2019-10-01
影响因子：
11
通讯作者：
Han, Feng
中科院分区：
文献类型：
--
作者：
Shao, Ling-Xiao;Jiang, Quan;Han, Feng
焦虑症是最常见的精神疾病，但其致病机制尚不清楚。在这里，我们报道了跨膜蛋白74 (TMEM74)，它包含两个假定的跨膜结构域，在大脑中表现出高水平的mRNA，与焦虑症的发病机制密切相关。焦虑患者血清中TMEM74水平降低，慢性应激小鼠基底外侧杏仁核（BLA）水平降低。此外，BLA锥体神经元中tmem74的基因缺失或选择性敲低会导致小鼠的焦虑样行为。BLA锥体神经元的全细胞记录显示，与野生型神经元相比，其超极化激活阳离子电流（Ih）更低，输入电阻和兴奋性更大。因此，在tmem74−/−小鼠的BLA中，超极化激活的环核苷酸门控1 （HCN1）通道的表面表达也较低。他们的电流阻滞剂ZD7288在野生型小鼠的BLA锥体神经元中模拟了这些作用，但在inTmem74 - / -小鼠中没有。与焦虑样行为的改善一致，Tmem74过表达恢复了Tmem74−/−和慢性应激小鼠BLA中的HCN1通道运输和锥体神经元兴奋性。从机制上讲，我们证明了Tmem74和HCN1之间的相互作用具有生理相关性，并且跨膜结构域1 （TM1）对于Tmem74的细胞膜定位增强eih至关重要。总之，我们的研究结果表明，Tmem74与HCN1偶联在焦虑的病理生理中起着关键作用，是焦虑障碍新疗法的潜在靶点。
Anxiety disorders are the most prevalent psychiatric disorders, but their pathogenic mechanism remains poorly understood. Here, we report that transmembrane protein 74 (TMEM74), which contains two putative transmembrane domains and exhibits high levels of mRNA in the brain, is closely associated with the pathogenesis of anxiety disorders. TMEM74 was decreased in the serum of patients with anxiety and the basolateral amygdaloid nucleus (BLA) in chronic stress mice. Furthermore, genetic deletion ofTmem74or selective knockdown ofTmem74in BLA pyramidal neurons resulted in anxiety-like behaviors in mice. Whole-cell recordings in BLA pyramidal neurons revealed lower hyperpolarization-activated cation current (Ih) and greater input resistance and excitability inTmem74−/−neurons than in wild-type neurons. Accordingly, surface expression of hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels was also lower in the BLA ofTmem74−/−mice. TheIhcurrent blocker ZD7288 mimicked these effects in BLA pyramidal neurons in wild-type mice but not inTmem74−/−mice. Consistent with the improvement in anxiety-like behaviors, Tmem74 overexpression restored HCN1 channel trafficking and pyramidal neuron excitability in the BLA ofTmem74−/−and chronic stress mice. Mechanistically, we demonstrate that interactions between Tmem74 and HCN1 are physiologically relevant and that transmembrane domain 1 (TM1) is essential for the cellular membrane localization of Tmem74 to enhanceIh. Together, our findings suggest that Tmem74 coupling with HCN1 acts as a critical component in the pathophysiology of anxiety and is a potential target for new treatments of anxiety disorders.