Progressive excitability changes in the medial entorhinal cortex in the 3xTg mouse model of Alzheimer’s disease pathology
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Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in hippocampus, but less is known about changes in medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at 3 and 10 months of age in the 3xTg mouse model of AD pathology, using male and female mice. At 3 months of age, before the onset of memory impairments, we found early hyperexcitability in intrinsic properties of MECII stellate and pyramidal cells, but this was balanced by a relative reduction in synaptic excitation (E) compared with inhibition (I; E/I ratio), suggesting intact homeostatic mechanisms regulating MECII activity. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable, and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsic and synaptic hyperexcitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this postsymptomatic time point, which may contribute to the emergence of memory deficits in AD. SIGNIFICANCE STATEMENT AD causes cognitive deficits, but the specific neural circuits that are damaged to drive changes in memory remain unknown. Using a mouse model of AD pathology that expresses both amyloid and tau transgenes, we found that neurons in the MEC have altered excitability. Before the onset of memory impairments, neurons in layer 2 of MEC had increased intrinsic excitability, but this was balanced by reduced inputs onto the cell. However, after the onset of memory impairments, stellate cells in MEC became further hyperexcitable, with increased excitability exacerbated by increased synaptic inputs. Thus, it appears that MEC stellate cells are uniquely disrupted during the progression of memory deficits and may contribute to cognitive deficits in AD.
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The 3×Tg-AD mouse model possesses three gene mutations associated with human familial Alzheimer's disease: human presenilin-1 M146V, human amyloid precursor protein Swedish, and human tau protein P301L.
“One commonly used animal model of AD is the triple transgenic mouse model (3×Tg-AD), which possesses three gene mutations associated with human familial AD: the human presenilin-1 M146V mutation, human amyloid precursor protein Swedish mutation, and human tau protein P301L mutation (Chen et al., 2023; Li et al., 2025).”
From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Chen et al., 2023
The discussion of the 3xTg model (p. 16) identifies the APP Swedish and PS1M146V mutations and the MAPTP301L tau transgene, supporting the list of three changes. It does not state that all three are human mutations associated with familial Alzheimer’s disease. (LLM, conf=0.83)
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Increased Hippocampal Excitability in the 3xTgAD Mouse Model for Alzheimer's Disease In Vivo
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Oxidation of K+ Channels in Aging and Neurodegeneration
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Aducanumab and the “post-amyloid” era of Alzheimer research?
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Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology
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Chronotate: An open-source tool for manual timestamping and quantification of animal behavior
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The 3xTg-AD Mouse Model: A Comprehensive Tool for Understanding Alzheimer’s Disease
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Inhibition of the GSK3β/Nav1.6 complex suppresses early‐stage Alzheimer's hyperexcitability
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A novel PGK1 activator improves Alzheimer’s disease by regulating glycolysis
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- Authors
- Chen, L., Christenson Wick, Z., Vetere, L. M., Vaughan, N., Jurkowski, A., Galas, A., Diego, K. S., Philipsberg, P. A., Soler, I., Feng, Y., Cai, D. J., & Shuman, T.
- Affiliations
- University of California, Irvine (US)
- Icahn School of Medicine at Mount Sinai (US)
- City University of New York (US)
- New York University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2023-09-15
- Volume
- 43
- Issue
- 44
- Pages
- 7441-7454
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC10621765
- OpenAlex
- W4386766499
- Cited by
- 21
- References
- 112
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 2
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- HHS | NIH | National Institute on Aging (RF1AG072497, F31AG069496)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01NS116357, R03NS111493, F32NS116416)
- HHS | NIH | National Institute of Mental Health (R01MH120162, DP2MH122399, R56MH132959)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, medial entorhinal cortex, neuronal excitability, 3xTg mouse model, stellate cells, pyramidal neurons, homeostatic regulation, memory impairment, hippocampus, sex differences, cognitive impairment, intrinsic excitability, layer II, layer III
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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