Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

Musial TF, Molina-Campos E, Bean LA, Ybarra N, Borenstein R, Russo ML, Buss EW, Justus D, Neuman KM, Ayala GD, Mullen SA, Voskobiynyk Y, Tulisiak CT, Fels JA, Corbett NJ, Carballo G, Kennedy CD, Popovic J, Ramos-Franco J, Fill M, Pergande MR, Borgia JA, Corbett GT, Pahan K, Han Y, Chetkovich DM, Vassar RJ, Byrne RW, Matthew Oh M, Stoub TR, Remy S, Disterhoft JF, Nicholson DA
Neurobiol Learn Mem. 2018 154: 141-157

PMID: 29906573 · PMCID: PMC6434702 · DOI:10.1016/j.nlm.2018.06.004

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.

Copyright © 2018. Published by Elsevier Inc.

MeSH Terms (14)

Action Potentials Aging Alzheimer Disease Animals CA1 Region, Hippocampal Channelopathies Disease Models, Animal Endoplasmic Reticulum Female Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Male Mice, Transgenic Neuronal Plasticity Pyramidal Cells

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