Variability in sub-threshold signaling linked to Alzheimer's disease emerges with age and amyloid plaque deposition in mouse ventral CA1 pyramidal neurons

Neurobiol Aging. 2021 Oct;106:207-222. doi: 10.1016/j.neurobiolaging.2021.06.018. Epub 2021 Jun 26.

Abstract

The hippocampus is vulnerable to deterioration in Alzheimer's disease (AD). It is, however, a heterogeneous structure, which may contribute to the differential volumetric changes along its septotemporal axis during AD progression. Here, we investigated amyloid plaque deposition along the dorsoventral axis in two strains of transgenic AD (ADTg) mouse models. We also used patch-clamp physiology in these mice to probe for functional consequences of AD pathogenesis in ventral hippocampus, which we found bears significantly higher plaque burden in the aged ADTg group compared to corresponding dorsal regions. Despite dorsoventral differences in amyloid load, ventral CA1 pyramidal neurons of aged ADTg mice exhibited subthreshold physiological changes similar to those previously reported in dorsal neurons, indicative of an HCN channelopathy, but lacked exacerbated suprathreshold accommodation. Additionally, HCN channel function could be rescued by pharmacological manipulation of the endoplasmic reticulum. These observations suggest that an AD-linked HCN channelopathy emerges in both dorsal and ventral CA1 pyramidal neurons, but that the former encounter an additional integrative obstacle in the form of reduced intrinsic excitability.

Keywords: Amyloid plaque; CA1; HCN channel; Patch-clamp; Store depletion-induced plasticity; Ventral hippocampus.

Publication types

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

MeSH terms

  • Aging / metabolism*
  • Alzheimer Disease / etiology*
  • Alzheimer Disease / metabolism*
  • Animals
  • CA1 Region, Hippocampal / cytology*
  • CA1 Region, Hippocampal / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Mice, Transgenic
  • Organ Size
  • Patch-Clamp Techniques
  • Plaque, Amyloid / metabolism*
  • Pyramidal Cells / metabolism*
  • Signal Transduction*

Substances

  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels