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

Matthew L. Russo, Elizabeth Molina-Campos, Natividad Ybarra, Annalise E. Rogalsky, Timothy F. Musial, Viviana Jimenez, Loreece G. Haddad, Yuliya Voskobiynyk, Gary X. D'Souza, Gabriel Carballo, Krystina M. Neuman, Dane M Chetkovich, M. Matthew Oh, John F. Disterhoft, Daniel A. Nicholson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)207-222
Number of pages16
JournalNeurobiology of Aging
Volume106
DOIs
StatePublished - Oct 2021

Keywords

  • Amyloid plaque
  • CA1
  • HCN channel
  • Patch-clamp
  • Store depletion-induced plasticity
  • Ventral hippocampus

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Clinical Neurology
  • Geriatrics and Gerontology

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