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Neurobiol Learn Mem. 2018 Oct;154:141-157. doi: 10.1016/j.nlm.2018.06.004. Epub 2018 Jun 12.

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

Author information

1
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
2
Neuronal Networks Group, Deutsches Zenstrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
3
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
4
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612, USA.
5
Department of Pathology, Rush University Medical Center, Chicago, IL 60612, USA.
6
Department of Pathology, Rush University Medical Center, Chicago, IL 60612, USA; Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA.
7
Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
8
Department of Neurosurgery, Rush University Medical Center, Chicago, IL 60612, USA.
9
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
10
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; Department of Neurosurgery, Rush University Medical Center, Chicago, IL 60612, USA.
11
Neuronal Networks Group, Deutsches Zenstrum für Neurodegenerative Erkrankungen, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany; Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud-Straβe 25, 53125 Bonn, Germany.
12
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: jdisterhoft@northwestern.edu.
13
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. Electronic address: dan_nicholson@rush.edu.

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.

KEYWORDS:

Array tomography; Carvedilol; Electron microscopy; Endoplasmic reticulum; HCN channel; Patch-clamp; TRIP8b

PMID:
29906573
PMCID:
PMC6434702
DOI:
10.1016/j.nlm.2018.06.004
[Indexed for MEDLINE]
Free PMC Article

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