AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice

Eric H. Chang, Mary J. Savage, Dorothy G. Flood, Justin M. Thomas, Robert B. Levy, Veeravan Mahadomrongkul, Tomoaki Shirao, Chiye Aoki, Patricio T. Huerta

Research output: Contribution to journalArticlepeer-review

Abstract

It is widely thought that Alzheimer's disease (AD) begins as a malfunction of synapses, eventually leading to cognitive impairment and dementia. Homeostatic synaptic scaling is a mechanism that could be crucial at the onset of AD but has not been examined experimentally. In this process, the synaptic strength of a neuron is modified so that the overall excitability of the cell is maintained. Here, we investigate whether synaptic scaling mediated by L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) contributes to pathology in double knockin (2 × KI) mice carrying human mutations in the genes for amyloid precursor protein and presenilin-1. By using whole-cell recordings, we show that 2 × KI mice exhibit age-related downscaling of AMPAR-mediated evoked currents and spontaneous, miniature currents. Electron microscopic analysis further corroborates the synaptic AMPAR decrease. Additionally, 2 × KI mice show age-related deficits in bidirectional plasticity (long-term potentiation and long-term depression) and memory flexibility. These results suggest that AMPARs are important synaptic targets for AD and provide evidence that cognitive impairment may involve downscaling of postsynaptic AMPAR function.

Original languageEnglish (US)
Pages (from-to)3410-3415
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number9
DOIs
StatePublished - Feb 28 2006

Keywords

  • Amyloid precursor protein
  • Glutamate
  • Presenilin

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice'. Together they form a unique fingerprint.

Cite this