Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10153658 | Neurobiology of Learning and Memory | 2018 | 44 Pages |
Abstract
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.
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Authors
Timothy F. Musial, Elizabeth Molina-Campos, Linda A. Bean, Natividad Ybarra, Ronen Borenstein, Matthew L. Russo, Eric W. Buss, Daniel Justus, Krystina M. Neuman, Gelique D. Ayala, Sheila A. Mullen, Yuliya Voskobiynyk, Christopher T. Tulisiak,