Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Yue Wang, Nigel H. Greig, Qian sheng Yu, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid β-peptide (Aβ). However, Aβ-independent effects of mutant PS1 on neuronal Ca2+ homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca2+chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3xTgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.

Original languageEnglish (US)
Pages (from-to)1061-1068
Number of pages8
JournalNeurobiology of Aging
Volume30
Issue number7
DOIs
StatePublished - Jul 2009
Externally publishedYes

Keywords

  • Alzheimer disease
  • Butyrylcholinesterase
  • LTP
  • NMDA
  • PS1KI mice

ASJC Scopus subject areas

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

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