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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels