Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, USA.
Department of Neurology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA.
Sci Transl Med. 2021 Nov 24;13(621):eabl4580. doi: 10.1126/scitranslmed.abl4580.
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.
超极化激活环核苷酸门控 (HCN) 通道调节神经元兴奋性，是治疗重度抑郁症 (MDD) 的潜在靶点。这些通道受细胞内环腺苷酸 (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不清楚。在这项研究中，我们使用化学遗传学技术在小鼠中研究了海马 cAMP 信号对行为的作用。急性增加 cAMP 通过增加 HCN 功能来限制空间记忆和动机行为。然而，慢性升高的 cAMP 通过破坏 HCN 与四肽重复含 Rab8b 相互作用蛋白 (TRIP8b) 的相互作用，从而限制 HCN 通道的表面转运，TRIP8b 是一种辅助亚基。背海马区慢性升高的 cAMP 也足以挽救慢性应激诱导的小鼠认知缺陷。这些结果揭示了 HCN 通道表面表达的一种具有行为相关性的调节形式，有可能成为与慢性应激相关的认知缺陷的治疗靶点。
