Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels regulate neuronal excitability and represent a possible therapeutic target for major depressive disorder (MDD). These channels are regulated by intracellular cyclic adenosine monophosphate (cAMP). However, the relationship between cAMP signaling and the influence of HCN channels on behavior remains opaque. In this study, we investigated the role of hippocampal cAMP signaling on behavior using chemogenetic technology in mice. Acutely increasing cAMP limited spatial memory and motivated behavior by increasing HCN function. However, chronically elevated cAMP limited surface trafficking of HCN channels by disrupting the interaction between HCN and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit. Chronically increased cAMP in the dorsal hippocampus was also sufficient to rescue cognitive deficits induced by chronic stress in mice. These results reveal a behaviorally relevant form of regulation of HCN channel surface expression that has potential as a therapeutic target for cognitive deficits related to chronic stress.

中文翻译：

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海马 cAMP 在两个时间尺度上调节 HCN 通道功能，对动物行为有不同的影响

超极化激活的环核苷酸门控 (HCN) 通道调节神经元的兴奋性，并代表了重度抑郁症 (MDD) 的可能治疗靶点。这些通道受细胞内环磷酸腺苷 (cAMP) 的调节。然而，cAMP 信号与 HCN 通道对行为的影响之间的关系仍然不透明。在这项研究中，我们使用化学遗传学技术研究了海马 cAMP 信号传导对小鼠行为的作用。通过增加 HCN 功能急剧增加 cAMP 会限制空间记忆和动机行为。然而，长期升高的 cAMP 通过破坏 HCN 和含有四三肽重复的 Rab8b 相互作用蛋白 (TRIP8b)（一种辅助亚基）之间的相互作用来限制 HCN 通道的表面运输。背侧海马中长期增加的 cAMP 也足以挽救由小鼠慢性压力引起的认知缺陷。这些结果揭示了一种行为相关的 HCN 通道表面表达调节形式，它有可能成为与慢性压力相关的认知缺陷的治疗靶点。