AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice
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.
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- Authors
- Chang, E. H., Savage, M. J., Flood, D. G., Thomas, J. M., Levy, R. B., Mahadomrongkul, V., Shirao, T., Aoki, C., & Huerta, P. T.
- Affiliations
- Cornell University (US)
- Department of Neurobiology, Cephalon Inc., West Chester, PA 19380; and
- New York University (US)
- Gunma University (JP)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-02-21
- Volume
- 103
- Issue
- 9
- Pages
- 3410-3415
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2022025213
- Cited by
- 225
- References
- 12
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 3 · 2023: 10 · 2022: 10 · 2021: 16 · 2020: 13 · 2019: 12 · 2018: 11 · 2017: 12 · 2016: 9 · 2015: 6 · 2014: 5 · 2013: 8 · 2012: 13
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Federation for Aging Research
- York University
- National Eye Institute (R01EY013145, R01EY008055, P30EY013079)
- National Institute of Neurological Disorders and Stroke (R01NS041091, R25NS080686)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, AMPA receptors, synaptic scaling, homeostatic synaptic scaling, amyloid precursor protein, presenilin 1, miniature synaptic currents, long-term potentiation, long-term depression, bidirectional synaptic plasticity, memory flexibility, synaptic dysfunction
- MeSH terms
- Aging, Alzheimer Disease, Animals, Electrophysiology, Hippocampus, Memory, Mice, Transgenic, Microscopy, Electron, Neuronal Plasticity, Synapses, Down-Regulation, Amyloid beta-Peptides, Receptors, AMPA, Mice
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