Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Neuronal Networks Group, Deutsches Zenstrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
Neurobiol Learn Mem. 2018 Oct;154:141-157. doi: 10.1016/j.nlm.2018.06.004. Epub 2018 Jun 12.
Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.
电压门控离子通道对于神经元整合至关重要。然而，这些通道中的一些在几种神经疾病中被错误调节，导致神经元中出现功能增益和功能丧失的通道病。我们使用几种阿尔茨海默病（AD）的转基因小鼠模型发现，超极化激活、环核苷酸门控（HCN）通道强烈影响的阈下电压信号在海马 CA1 锥体神经元中随着年龄的增长而逐渐恶化。转基因小鼠中通过 HCN 通道的退化信号伴随着其非均匀树突表达的与年龄相关的整体丧失。通过内质网（ER）靶向的各种药理学制剂可以恢复 HCN 通道病的异常信号及其定位错误。我们对 HCN 通道病的挽救有助于提供分子细节，说明 ER 靶向药物对 AD 小鼠模型发病机制和突触/认知缺陷的有利影响，并暗示它们可能对与 HCN 通道病相关的神经疾病有有益的影响。
