Synaptic deficits in layer 5 neurons precede overt structural decay in 5xFAD mice
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Synaptic decay and neurodegeneration are hallmarks of Alzheimer's disease that are thought to precede dementia. Recently, we have reported that the first signs of neuritic dystrophy in a new transgenic mouse model of familial Alzheimer's disease (FAD) called the "5xFAD" are axonal dystrophy followed by loss of spines on basal dendrites. The 5xFAD mouse has profound loss of layer 5 neurons by 12months, and these initial structural insults appear between 4 and 6months of age. Here, we test, for the first time, if synaptic failure of layer 5 neurons in the 5xFAD mouse precedes these structural changes. We used longitudinal, in vivo two-photon fluorescence imaging of bigenic 5xFAD/YFP mice to assess the overall structural stability of layer 5 neurons in young mice (age less than 14weeks). We found these neurons to be structurally and morphologically sound. In parallel, we used in vitro, whole-cell patch clamp electrophysiology of layer 5 pyramidal neurons, from mice aged 8-12weeks, to reveal significant pre- and postsynaptic defects in these cells. Thus our data suggest that layer 5 neurons in the 5xFAD mouse model have synaptic deficits at an early time point, before any overt structural dystrophy, and that such synaptic failure, with co-temporal biochemical changes, may be an early step in neuronal loss.
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5xFAD mice display synaptic deficits and neuronal loss at later stages of disease.
“in addition to synaptic deficits and neuronal loss at later stages of the disease [49, 45].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [49]
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- Authors
- Buskila, Y., Crowe, S. E., & Ellis-Davies, G. C. R.
- Affiliations
- Western Sydney University (AU)
- Icahn School of Medicine at Mount Sinai (US)
- ORCID
- Buskila, Y.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 254
- Pages
- 152-159
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC4078998
- OpenAlex
- W1995690139
- Cited by
- 77
- References
- 37
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 12 · 2020: 11 · 2019: 6 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 1
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (GM053395, R01GM053395)
- National Institute of Neurological Disorders and Stroke (R01NS069720, NS069720)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- 5xFAD mice, Alzheimer's disease, layer 5 pyramidal neurons, synaptic dysfunction, neuronal loss, axonal dystrophy, dendritic spine loss, neuritic dystrophy, early neurodegeneration, familial Alzheimer's disease, two-photon imaging, whole-cell patch clamp
- MeSH terms
- Alzheimer Disease, Animals, Cerebral Cortex, Disease Models, Animal, Longitudinal Studies, Mice, Transgenic, Neurons, Organ Culture Techniques, Synapses, Mice
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