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

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, Jasmine A. Fels, Nicola J. Corbett, Gabriel Carballo, Colette D. Kennedy, Jelena Popovic, Josefina Ramos-Franco, Michael FillMelissa R. Pergande, Jeffrey A. Borgia, Grant T. Corbett, Kalipada Pahan, Ye Han, Dane M. Chetkovich, Robert J. Vassar, Richard W. Byrne, M. Matthew Oh, Travis R. Stoub, Stefan Remy, John F. Disterhoft*, Daniel A. Nicholson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)141-157
Number of pages17
JournalNeurobiology of Learning and Memory
Volume154
DOIs
StatePublished - Oct 2018

Keywords

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

ASJC Scopus subject areas

  • Experimental and Cognitive Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

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