So Tsz Wei, Choi Hoi Yi, Xu Haoyu, Zhu Jinwei, Shi Lei, Ip Jacque Pak Kan
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai 200240, China.
IBRO Neurosci Rep. 2025 Apr 4;18:644-656. doi: 10.1016/j.ibneur.2025.03.008. eCollection 2025 Jun.
The hippocampus is a complex structure consisting of the dentate gyrus (DG), cornu ammonis (CA) and the subiculum. CA1 is further subdivided into the ventral (vCA1) and dorsal (dCA1) compartments, with dCA1 believed to be crucial in spatial learning and memory as well as cognitive processing. Although dCA1 was traditionally thought to be not likely relevant to affective diseases, recent studies suggest otherwise. In fact, it has been found that diseases including certain types of post-traumatic stress disorder (PTSD), depression and epilepsy may be attributed to channelopathies in dCA1, particularly that of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. However, it remains unclear how disruptions of HCN transcription, post-transcriptional modification and activation kinetics are related to changes of downstream structures along neural circuits. Their effect on behavioural changes and disease development, as well as the corresponding potential therapeutic strategies implicated in the findings have not been extensively studied as well. With the existing research gap and the significant clinical implications of dCA1 HCN channelopathies, the mechanisms of how defects of these channels result in brain disorders including PTSD, depression and temporal lobe epilepsy are worthy of further investigation. Therefore, in this review, we summarize the recent findings on the involvement of dCA1 HCN channelopathies in brain disorders after providing an outline on the neuroanatomy and functional connectivity of dCA1, and the features of HCN channels in that region. We also propose future directions of molecular and systems neuroscience studies, as well as the translational research on potential therapeutics that address the brain disorders related to dCA1 HCN channelopathies.
海马体是一个复杂的结构，由齿状回（DG）、海马角（CA）和下托组成。CA1进一步细分为腹侧（vCA1）和背侧（dCA1）区室，人们认为dCA1在空间学习和记忆以及认知加工中至关重要。尽管传统上认为dCA1与情感性疾病不太可能相关，但最近的研究表明并非如此。事实上，已经发现包括某些类型的创伤后应激障碍（PTSD）、抑郁症和癫痫在内的疾病可能归因于dCA1中的离子通道病，特别是超极化激活的环核苷酸门控（HCN）通道的离子通道病。然而，目前尚不清楚HCN转录、转录后修饰和激活动力学的破坏如何与神经回路下游结构的变化相关。它们对行为变化和疾病发展的影响，以及研究结果中涉及的相应潜在治疗策略也尚未得到广泛研究。鉴于现有的研究空白以及dCA1 HCN通道病的重大临床意义，这些通道的缺陷如何导致包括PTSD、抑郁症和颞叶癫痫在内的脑部疾病的机制值得进一步研究。因此，在本综述中，我们在概述dCA1的神经解剖学和功能连接以及该区域HCN通道的特征之后，总结了关于dCA1 HCN通道病参与脑部疾病的最新发现。我们还提出了分子和系统神经科学研究的未来方向，以及针对与dCA1 HCN通道病相关的脑部疾病的潜在治疗方法的转化研究。
