Mechanisms Underlying Basal and Learning-Related Intrinsic Excitability in a Mouse Model of Alzheimer's Disease

Neurobiol Aging. 2011 Aug;32(8):1452-65. doi: 10.1016/j.neurobiolaging.2009.09.003. Epub 2009 Oct 14.

Abstract

Accumulations of β-amyloid (Aβ) contribute to neurological deficits associated with Alzheimer's disease (AD). The effects of Aβ on basal neuronal excitability and learning-related AHP plasticity were examined using whole-cell recordings from hippocampal neurons in the 5XFAD mouse model of AD. A robust increase in Aβ42 (and elevated levels of Aβ38-40) in naïve 5XFAD mice was associated with decreased basal neuronal excitability, evidenced by a select increase in Ca(2+)-sensitive afterhyperpolarization (AHP). Moreover, trace fear deficits observed in a subset of 5XFAD weak-learner mice were associated with a greater enhancement of the AHP in neurons, as compared to age-matched 5XFAD learner and 5XFAD naïve mice. Importantly, learning-related plasticity of the AHP remained intact in a subset of 5XFAD mice that learned trace fear conditioning to a set criterion. We show that APP-PS1 mutations enhance Aβ and disrupt basal excitability via a Ca(2+)-dependent enhancement of the AHP, and suggest disruption to learning-related modulation of intrinsic excitability resulted, in part, from altered cholinergic modulation of the AHP in the 5XFAD mouse model of AD (170 of 170).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / physiopathology*
  • Alzheimer Disease / psychology
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / physiology
  • Animals
  • Calcium / metabolism
  • Conditioning, Psychological / physiology
  • Disease Models, Animal
  • Humans
  • Learning / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Organ Culture Techniques
  • Presenilin-1 / genetics*
  • Presenilin-1 / physiology

Substances

  • Amyloid beta-Protein Precursor
  • PSEN1 protein, human
  • Presenilin-1
  • Calcium